Is BRCA2 p.Ser142Ile (c.425G>T) pathogenic?

BRCA2 p.Ser142Ile (c.425G>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-13). AlphaMissense: ambiguous (0.4024); Very rare (popmax 0.00167%, amr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Ser142Ile (c.425G>T)?

BRCA2 p.Ser142Ile (c.425G>T) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ser142Ile (c.425G>T) in the general population?

BRCA2 p.Ser142Ile (c.425G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.Ser142Ile (c.425G>T)?

AlphaMissense predicts ambiguous (score 0.4024) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser142Ile

c.425G>T · rs397507713 · VCV51618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.4024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.4024	ambiguous · top 10% in BRCA2
REVEL	0.165	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.97	donor loss · deltas
Pangolin	Δ0.78	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,886 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000259% 4/1,545,108 alleles · very rare exomes 4/1,392,954 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,886
European (non-Finnish)	0.000268%	372,845

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.Ser142Ile
Coding: c.425G>T
MANE Select: NM_000059
dbSNP: rs397507713
Type: single nucleotide variant
Location: chr13:32325184 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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

Disease context

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

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

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser142Arg Uncertain significance ★ ⚠ same residue
BRCA2 p.Ser142Asn 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
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-ser142ile (accessed [today's date]).

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