13-32376760-T-G

Variant names:

• chr13-32376760-T-G
• rs28897753
• NM_000059.4:c.8723T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.8723T>G​(p.Val2908Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2908M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: 4.83
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 13-32376760-T-G is Benign according to our data. Variant chr13-32376760-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52662.

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.8723T>G	p.Val2908Gly	missense	Exon 21 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8723T>G	p.Val2908Gly	missense	Exon 21 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8723T>G	p.Val2908Gly	missense	Exon 21 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.8723T>G	p.Val2908Gly	missense	Exon 21 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8723T>G	p.Val2908Gly	missense	Exon 21 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8354T>G	p.Val2785Gly	missense	Exon 21 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000159 AC: 4 AN: 251276 AF XY: 0.0000221

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000399 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Oct 23, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 15, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 04, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Feb 12, 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.8723T>G (p.Val2908Gly) results in a non-conservative amino acid change located in the BRCA2, OB2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 252228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8723T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Wu_2005, Farrugia_2008, van Harssel_2010, Konecny_2011, Lee_2008, Przychodzen_2018, Kraemer_2019, Rizzolo_2019, Machackova_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent case-control study in breast cancer patients showed that this variant had similar frequency in cases and controls (Dorling_2021, LOVD database). A co-occurrence with another pathogenic variant has also been reported (BRCA1 c.4689C>G, p.Tyr1563X; NHGRI BIC database), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results, which include evidence from HDR assays, showed no damaging effect of this variant (e.g., Wu_2005, Farrugia_2008, Acedo_2014, Guidugli_2018, Hart_2019, Richardson_2021, Hu_2022). A drug sensitivity study showed the variant had a damaging effect on cell viability (e.g., Ikegami_2020), however, it was not clear how this effect may impact cancer pathogenesis. The following publications have been ascertained in the context of this evaluation (PMID: 25382762, 33471991, 18451181, 29394989, 29884841, 35736817, 32444794, 21203900, 31422574, 18284688, 31409081, 29416752, 33609447, 30613976, 15695382, 19949876). ClinVar contains an entry for this variant (Variation ID: 52662). Based on the evidence outlined above, the variant was classified as likely benign.

not provided Benign:3

Jun 30, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4

Aug 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

Sep 28, 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.

May 02, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 10, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000059.4(BRCA2):c.8723T>G (p.Val2908Gly) has been reported to ClinVar as Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 52662 as of 2024-08-01). The p.Val2908Gly variant is observed in 4/113,642 (0.0035%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Val2908Gly variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between valine and glycine. The gene BRCA2 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.00. The gene BRCA2 contains 146 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Val2908Gly missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 2908 of BRCA2 is conserved in all mammalian species. The nucleotide c.8723 in BRCA2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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 p.Val2908Gly variant was identified in 2 of 1782 proband chromosomes (frequency: 0.0001) from individuals or families with breast/ovarian cancers (Konecny 2011, van Harssel 2010). In functional studies comparing mutant and wildtype forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, genome instability and centriole amplification, the variant was comparable to wildtype or demonstrated no impaired BRCA2 function (Wu 2005, Farrugia 2008). In a computational multifactorial model combining three independent measures (co-occurrence of variant with known deleterious mutations, personal and family history of cancer, and co-segregation with disease), the variant was found to be neutral (Easton 2007). Another computational method looking at probabilistic likelihood ratio of variant (whether missense variant impairs protein function), was inconclusive (Karchin 2008). The variant was also identified in dbSNP (ID: rs28897753) “With other allele”, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 33026 individuals from a population of European (Non-Finnish) individuals (frequency: 0.00003), Clinvitae database (classifications likely benign and conflicting interpretations of pathogenicity), Fanconi Anemia Mutation Database (LOVD) and ARUP Laboratories BRCA Mutations Database (classified as likely not pathogenic or of little clinical significance), the ClinVar database (classified as likely benign by Ambry Genetics, GeneDX, Counsyl, Invitae, and Sharing Clinical Reports Project(derived from Myriad reports); and classified as uncertain significance by BIC), the BIC database (8x with unknown clinical importance, classification pending). The p.Val2908 residue is conserved across mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.060	T
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.58
MVP		0.91
MPC		0.16
ClinPred		0.93	D
GERP RS		5.3
gMVP		0.61
Mutation Taster		=53/47	polymorphism

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: rs28897753; hg19: chr13-32950897;