Is BRCA2 p.Met2676Thr (c.8027T>C) pathogenic?

BRCA2 p.Met2676Thr (c.8027T>C) is classified Benign/Likely benign in BRCA2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-05-20). AlphaMissense: likely benign (0.1207); Very rare (popmax 0.00203%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Met2676Thr (c.8027T>C)?

BRCA2 p.Met2676Thr (c.8027T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Met2676Thr (c.8027T>C) in the general population?

BRCA2 p.Met2676Thr (c.8027T>C) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Met2676Thr (c.8027T>C)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

BRCA2 p.Met2676Thr

c.8027T>C · rs80359038 · VCV38136

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.402	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	13.21	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,950 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00185% 27/1,461,718 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,165
Remaining individualsnot grpmax-eligible	0.0016%	62,496
Finnishnot grpmax-eligible	0.00156%	63,970
South Asian	0.0011%	91,064

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.

Variant & gene context

Gene: BRCA2
Protein: p.Met2676Thr
Coding: c.8027T>C
MANE Select: NM_000059
dbSNP: rs80359038
Type: single nucleotide variant
Location: chr13:32363229 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2676: the 'interaction with sem1' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast cancer breast-ovarian cancer, familial, susceptibility to, 2

Similar variants

BRCA2 p.Met2676Val Uncertain significance ★★ same residue
BRCA2 p.Met2676Leu Uncertain significance ★ 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
BRCA2 c.475+1G>A Pathogenic ★★★ same condition
BRCA2 c.475+1G>T 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-met2676thr (accessed [today's date]).

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