Is BRCA2 p.Lys2657Thr (c.7970A>C) pathogenic?

BRCA2 p.Lys2657Thr (c.7970A>C) is classified Uncertain significance in BRCA2 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-05-23). AlphaMissense: likely pathogenic (0.93); Very rare (popmax 0.00167%, amr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Lys2657Thr (c.7970A>C)?

BRCA2 p.Lys2657Thr (c.7970A>C) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Lys2657Thr (c.7970A>C) in the general population?

BRCA2 p.Lys2657Thr (c.7970A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Lys2657Thr (c.7970A>C)?

AlphaMissense predicts likely pathogenic (score 0.93) — an in-silico prediction, not a clinical call.

BRCA2 p.Lys2657Thr

c.7970A>C · rs1555286874 · VCV441298

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.93 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.93	likely pathogenic · top 1% in BRCA2
REVEL	0.799	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000657% 1/152,204 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PS3

Curation rationale (ClinGen, verbatim)

The c.7970A>C variant in BRCA2 is a missense variant predicted to cause substitution of lysine by threonine at amino acid 2657 (p.(Lys2657Thr)). This BRCA2 missense variant is within a key functional domain. The computational predictor BayesDel (noAF) gives a score of 0.27, indicating that impact on BRCA2 function via protein change is unclear (score range 0.18-0.30) and the SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 38417439, 39779857, 39779848). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.49 (based on Family History LR=1.49), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (PMID: 31853058). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA2
Protein: p.Lys2657Thr
Coding: c.7970A>C
MANE Select: NM_000059
dbSNP: rs1555286874
Type: single nucleotide variant
Location: chr13:32362687 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2657: the 'interaction with sem1' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

Similar variants

BRCA2 p.Lys2657= Likely benign ★★★ same residue
BRCA2 p.Lys2657Ter Pathogenic ★★ same residue
BRCA2 p.Lys2657Asn Uncertain significance ★★ same residue
BRCA2 p.Lys2657Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/brca2-p-lys2657thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown