13-32332309-T-G

Variant names:

• chr13-32332309-T-G
• rs28897705
• NM_000059.4:c.831T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BS1_Supporting BP1_Strong BP5 BS3

This summary comes from the ClinGen Evidence Repository: The c.831T>G variant in BRCA2 is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 277 (p.Asn277Lys). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00008331 in the European (non-Finnish) population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:33293522) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.06 (based on Cosegregation LR=0.3; Pathology LR=1.27; Co-occurrence LR=1.88; Family History LR=0.0888), within the thresholds for Moderate benign evidence (LR ≥0.05 & <0.23) (BP5_Moderate met; PMID:31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP1_Strong, BS3, BP5_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025568/MONDO:0012933/097

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:21
• Conservation: PhyloP100: 0.372
• Publications: 23 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.831T>G	p.Asn277Lys	missense	Exon 10 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.831T>G	p.Asn277Lys	missense	Exon 10 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.831T>G	p.Asn277Lys	missense	Exon 10 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.831T>G	p.Asn277Lys	missense	Exon 10 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.831T>G	p.Asn277Lys	missense	Exon 10 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.462T>G	p.Asn154Lys	missense	Exon 10 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000734 AC: 18 AN: 245138 AF XY: 0.0000830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000203 AC: 295 AN: 1454048 Hom.: 0 Cov.: 30 AF XY: 0.000191 AC XY: 138 AN XY: 723102

African (AFR) AF: 0.00 AC: 0 AN: 33082

American (AMR) AF: 0.00 AC: 0 AN: 43332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.000262 AC: 291 AN: 1108720

Other (OTH) AF: 0.0000666 AC: 4 AN: 60104

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000907 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Benign

Submissions summary: Uncertain:6 Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:7

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 17, 2024

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 16, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 16, 2025

Dipartimento Di Medicina Di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.831T>G (p.Asn277Lys) in the BRCA2 gene is located in exon 7 and results in the substitution of asparagine with lysine at codon 277. The affected residue is moderately conserved, and the change from a neutral polar to a basic amino acid may have a limited structural impact. However, in silico prediction tools such as BayesDel and REVEL indicate a tolerated or benign effect on BRCA2 protein function. To date, no strong clinical or functional evidence supports pathogenicity. Based on currently available information, this variant is interpreted as likely benign.

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2 Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 15, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.831T>G; p.Asn277Lys variant (rs28897705) is reported in the literature in individuals affected with breast, ovarian, prostate, or pancreatic cancer, although it was not demonstrated to be disease-causing (Kote-Jarai 2011, Schubert 2017, Schwartz 2019, van der Hout 2006). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (19/127296 alleles) in the Genome Aggregation Database. The asparagine at codon 277 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with predictions, one study observed the p.Asn277Lys variant disrupted interactions with factors involved with cytokinesis, and its expression in cultured cells correlated with a higher percentage of multinucleate cells (Mondal 2012), although the clinical significance of these observations has not been demonstrated. Due to limited information, the clinical significance of the p.Asn277Lys variant is uncertain at this time. References: Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105(8):1230-1234. Mondal G et al. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev Cell. 2012;23(1):137-152. Schubert S et al. GT198 (PSMC3IP) germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families. Genes Cancer. 2017;8(1-2):472-483. Schwartz M et al. Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort. Clin Genet. 2019;96(6):579-584. van der Hout AH et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006;27(7):654-666.

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16683254, 21952622, 28435519, 31432501, 22771033, 18724707, 10923033, 21533266, 27153395, 24817641, 25348012, 22476429, 31131967)

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1 Benign:3

May 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.831T>G (p.Asn277Lys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 7.3e-05 in 245138 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.831T>G has been reported in individuals affected with breast, ovarian, and other cancers, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variants have been reported (UMD: BRCA2 c.5909C>A, p.Ser1970X; BIC: BRCA1 c.2685_2686delAA, p.Pro897Lysfs; internal sample from a male patient: BRCA2 c.5386_5387delGA, p.Asp1796fsX10), providing supporting evidence for a benign role. Moreover, a recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). An experimental study determined the variant to be 'functional' based on cell survival and drug sensitivity assay results (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 21952622, 22476429, 18724707, 16683254, 22771033, 25348012, 24817641, 21533266, 27153395, 28435519, 30086788, 31432501, 31112341, 32438681, 33293522, 34597585). ClinVar contains an entry for this variant (Variation ID: 38152). Based on the evidence outlined above, the variant was classified as likely benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report identified this varint in a prostate cancer cohort - reported as unclassified variant; ClinVar: 3 VUS, 2 LB/B

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

Jan 13, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Jun 25, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Breast and/or ovarian cancer Uncertain:1

Feb 10, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2-related cancer predisposition Benign:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.831T>G variant in BRCA2 is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 277 (p.Asn277Lys). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.00008331 in the European (non-Finnish) population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to <= 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.06 (based on Cosegregation LR=0.3; Pathology LR=1.27; Co-occurrence LR=1.88; Family History LR=0.0888), within the thresholds for Moderate benign evidence (LR >=0.05 & <0.23) (BP5_Moderate met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP1_Strong, BS3, BP5_Moderate).

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Asn277Lys variant was identified in 1 of 8048 proband chromosomes (frequency: 0.0001) from individuals or families with breast and ovarian cancer (van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs28897705) as With other allele, ClinVar (conflicting interpretations of pathogenicity), Clinvitae (conflicting interpretations of pathogenicity), COGR (uncertain significance), MutDB, LOVD 3.0 (26X), UMD-LSDB (16X likely neutral), BIC Database (12X unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang Colon Cancer Databases. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.5909C>A (p.Ser1970X)), increasing the likelihood that the p.Asn277Lys variant does not have clinical significance. In addition, the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4042delT (p.Cys1348ValfsX26)) in on individual from our laboratory, increasing the likelihood that the p.Asn277Lys variant does not have clinical significance. The variant was identified in control databases in 18 of 271412 chromosomes at a frequency of 0.000066 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The functional study by Mondal (2012) suggested that the variant protein disrupted protein interactions, resulting in cytokinetic defects, but had no effect on BRCA2-dependent homologous recombination. The p.Asn277 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Hereditary breast ovarian cancer syndrome Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.37
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.089
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.072	T
Vest4		0.39
MutPred		0.41		Gain of solvent accessibility (P = 0.0105)
MVP		0.90
MPC		0.074
ClinPred		0.27	T
GERP RS		4.6
gMVP		0.13
Mutation Taster		=96/4	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28897705; hg19: chr13-32906446;