BRCA2

Final classification

Likely Benign

BRCA2 c.4183G>T · p.Ala1395Ser

BRCA2

PP4 (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 supporting threshold.

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.4183G>T

Consequence

N/A

GRCh38

chr13:32338538 G>T

GRCh37

chr13:32912675 G>T

Basis Likely Benign: conflicting-evidence net score -3 (PP4 Supporting +1, BP1 Strong -4) falls in the -6 to -2 Likely Benign range. ▾

Likely Benign: conflicting-evidence net score -3 (PP4 Supporting +1, BP1 Strong -4) falls in the -6 to -2 Likely Benign range.

Classification rationale

PP4 BP1 Likely Benign

BRCA2 c.4183G>T

PP4 (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 supporting threshold. BP1 (Strong): missense p.Ala1395Ser lies outside BRCA2's clinically important functional domains with no predicted splicing impact (SpliceAI max delta 0.00). Overall Likely Benign: conflicting-evidence point scoring (PP4 +1, BP1 -4, net -3) places the variant in the -6 to -2 Likely Benign range.

PP4 + BP1 → Likely Benign

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PP4 supporting Pathogenic

Met (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 threshold.

ENIGMA BRCA1/BRCA2 VCEP specification v1.2 (CSPEC 1535438831) PP4 rule: 'Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. PP4 - LR >=2.08' (Supporting); neutral zone 'Combined LR >0.48 and <2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable)'.Parsons et al. 2019 (PMID:31131967) Supplementary Table 1 (HUMU-40-1557-s001.xlsx, sheet 1): BRCA2 c.4183G>T, p.Ala1395Ser - pathology LR 1.07, co-occurrence LR 1.0246153856, family history LR 2.0294847967, Combined LR (Odds for Causality) 2.2250022419453646, prior 0.02, posterior 4.3435864217950808E-2 (IARC 'Uncertain'). Combined LR >=2.08 -> PP4 Supporting.Li et al. 2020 (PMID:31853058) clinical-history LR table (vcep_pmid_31853058_brca2_clinical_history_lr): c.4183G>T LR = 0.7929228517802025 (N=1 proband) - neutral zone, component not applied to avoid double counting family/personal history already integrated in the combined LR.

cspec ↗PMID:31131967 ↗PMID:31853058 ↗

✓

BP1 strong Benign

Met (Strong): missense p.Ala1395Ser lies outside BRCA2's functional domains with SpliceAI max delta 0.00.

ENIGMA BRCA1/BRCA2 VCEP specification v1.2 (cspec, doc 1535438831): BP1_Strong rule - missense variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI <= 0.1); domains defined as BRCA2 PALB2 binding domain aa 10-40 and BRCA2 DNA binding domain aa 2481-3186.SpliceAI lookup (spliceai): max delta score = 0.00 <= 0.1 - no predicted splicing impact.Variant normalization (prefetch.json / case_summary.json): p.Ala1395Ser; residue 1395 is not within aa 10-40 or aa 2481-3186.

cspec ↗spliceai ↗PMID:31911673 ↗

Assessed · not applied

Pathogenic

PS1 Not met: no pathogenic or likely pathogenic variant producing the same p.Ala1395Ser change exists (0 comparator candidates).

PS2 Not assessed: no parental testing or documentation of de novo occurrence was available.

PS3 Not met: no well-established functional studies supporting a damaging effect exist for this variant.

PS4 Not assessed: no case-control or prevalence data for this exact variant was available.

PM2 Not met: present in gnomAD v4.1 (AF 1.7e-06), so the strict absence requirement of PM2 is not demonstrated.

PM6 Not assessed: no evidence that the variant arose de novo.

PP1 Not assessed: no family segregation data or quantitative co-segregation likelihood ratio was available.

PP3 Not met: BayesDel no-AF -0.32 falls below the 0.30 threshold and SpliceAI max delta 0.00 below 0.2.

Benign

BA1 Not met: gnomAD FAF 2.8e-07 is far below the >0.1% BA1 threshold.

BS1 Not met: gnomAD FAF 2.8e-07 is below even the 0.002% BS1-Supporting threshold.

BS2 Not assessed: no proband phenotype data to score the ENIGMA BS2 points table.

BS3 Not met: no well-established functional assay demonstrates no damaging effect on protein function.

BS4 Not assessed: no co-segregation or non-segregation likelihood ratio data was available.

BP4 Not met: p.Ala1395Ser lies outside the BRCA2 functional domains, failing BP4's domain-location requirement.

BP5 Not met: combined LR 2.225 is in the pathogenic direction, above the <=0.48 BP5 threshold.

N/A · 11 PVS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.24747e-06; MAF= 0.00012%, 2/1603248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.70022e-06; MAF= 0.00017%, 2/1176318 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,603,248
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,176,318

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 96805)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.099. BayesDel score = -0.321456.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & References.

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

PMID 31131967 ↗ · Parsons MT et al. · 2019 Sep CLINVAR · splicing rna

Searched

c.4183G>Tp.Ala1395SerA1395S4183

Found

ENIGMA large-scale multifactorial likelihood analysis (Parsons et al. 2019). Direct lookup of BRCA2 c.4183G>T (p.Ala1395Ser) in the accompanying supplementary workbook (HUMU-40-1557-s001.xlsx): no BRCA2 row exists in Supplementary Table 1 'All Data' - the only c.4183G>T / p.(Ala1395Ser) row is BRCA1 (legacy description 4411G>T, combined LR 2.225, prior 0.02, posterior 0.043, IARC Uncertain). Supplementary Table 2 'Data Sources' lists BRCA2 c.4183G>T twice (source 'Easton et al 2007 dataset' and source 'Edinir Palmero') with EMPTY co-segregation family counts (one family-history-score count and one breast-tumour count respectively). No combined LR or co-segregation LR is therefore available for BRCA2 c.4183G>T, so PP1/BS4 cannot be quantified from this resource.

Variant

✓ Names this variant — characterised directly

Applied to

→PP4 supporting

Combined LR 2.225 for the exact variant (in companion SuppT1) meets the ENIGMA PP4 Supporting threshold of LR >=2.08.

Source: 'Easton et al 2007 dataset', Gene: 'BRCA2', Variant: 'c.4183G>T', Co-Segregation Family Count: (empty), Breast Tumour Count: (empty), Family History Score Family Count: '1' | Source: 'Edinir Palmero', Gene: 'BRCA2', Variant: 'c.4183G>T', Co-Segregation Family Count: (empty), Breast Tumour Count: '1', Family History Score Family Count: (empty)

Location HUMU-40-1557-s001.xlsx, Supplementary Table 2 'Data Sources' rows 708 and 1263 (columns: Source, Gene, Variant, Co-Segregation Family Count, Breast Tumour Count, Family History Score Family Count); absence of a BRCA2 row verified across Supplementary Table 1 'All Data' · Context ENIGMA multifactorial likelihood model for BRCA1/BRCA2 missense and splice variants combining segregation, pathology, co-occurrence, family history and case-control components with prior probability of pathogenicity and IARC 5-class output · full text

Rule & framework references · cited for criterion definitions, not variant evidence

31853058 ↗ Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR