Variant rs431825381 details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0309 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9945del	p.Glu3316AsnfsTer2	frameshift_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9945del	p.Glu3316AsnfsTer2	frameshift_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251220

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 05, 2019	Premature stop codon is located between the recognised high-risk truncating variant c.9924C>G (p.Tyr3308Ter) and the known low-risk truncating variant c.9976A>T (p.Lys3326Ter). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	Frameshift variant predicted to result in protein truncation as the last 103 amino acids are replaced with 1different amino acid; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.10173delA; This variant is associated with the following publications: (PMID: 25136594, 16912212) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 08, 2023	This variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. However, this variant occurs at the end of the BRCA2 transcript and the functional and clinical significance of the residues that would be lost are unknown (PMID: 18317453 (2008), 10570174 (1999) and ENIGMA (https://enigmaconsortium.org/)). In the published literature, this variant has been reported in an individual with breast cancer (PMID: 29337092 (2018)) and in an unaffected individual (PMID: 16912212 (2006)). Published functional studies showed that this variant does not significantly affect BRCA2 protein function (PMID: 29988080 (2019)). The frequency of this variant in the general population, 0.0002 (5/24898 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2023	The c.9945delA variant, located in coding exon 26 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9945, causing a translational frameshift with a predicted alternate stop codon (p.E3316Nfs*2). This alteration occurs at the 3' terminus of BRCA2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 102 amino acids of the protein. The exact functional effect of this alteration is unknown. This alteration has was reported in 1 of 674 healthy control women without breast cancer who participated in a multi-center population-based case-control study, but was not seen in any of the 1628 women with breast cancer (Malone KE et al. Cancer Res., 2006 Aug;66:8297-308). This alteration was identified in an individual diagnosed with breast cancer (Copson ER et al. Lancet Oncol, 2018 02;19:169-180). One study found this variant to be functionally sufficient in a BRCA2-null mouse embryonic stem cell complementation assay, a homology-directed repair (HDR) assay, and a cisplatin sensitivity assay (Mesman RLS et al. Genet Med, 2019 02;21:293-302). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2020	This variant deletes 1 nucleotide in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal at the carboxyl-terminus of the protein. This truncation is not expected to trigger nonsense-mediated decay. Functional studies using BRCA2-deficient mouse embryonic stem cells reported this variant protein to have intermediate activities in complementation of cell viability, sensitivity to DNA damaging agents and homology-directed DNA repair assays with repair activity that are comparable to likely neutral control variants (PMID: 18607349, 29988080). This variant has been observed in a breast cancer case-control study in an unaffected control and absent in affected individuals (PMID: 16912212). This variant has been identified in 5/282368 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 30, 2021

Variant summary: BRCA2 c.9945delA (p.Glu3316AsnfsX2) results in a premature termination codon. This variant is located in close proximity to another variant suggested in the literature to be a polymorphism (c.9976A>T, p.Lys3326X; classified as normal variant in our internal database). Other truncations downstream of this position have been classified by our laboratory ranging from VUS to Normal (Possibly Normal (c.9997_9998delCT, p.Leu3333fsX4); VUS (c.10024G>T, p.Glu3342X); Normal (c.10095delinsGAATTATATCT, p.Ser3366fsX4). The variant allele was found at a frequency of 1.6e-05 in 254490 control chromosomes (gnomAD and publication data). Additionally, it is reported in NHLBI Exome Sequencing Project in homozygous state in two individuals of African American origin; however, data from this project are included in gnomAD database and no report of homozygous occurrences exists in the specific database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9945delA has been reported in the literature in individuals affected with breast cancer (Copson_2018, Walsh_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Experimental evidence evaluating an impact on protein function did not provide strong evidence for pathogenicity of this variant (the variant showed 63% homology directed repair capacity relative to the levels observed in wild type and also, displayed cisplatin sensitivity of 61% compared to the wild type in a cell survival assay, Mesman_2018). Seven ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2023

The BRCA2 c.9945delA variant is predicted to result in a frameshift and premature protein termination (p.Glu3316Asnfs*2). This variant (also known as 9940delA, K3314fs and p.Lys3315fs) has been reported in both affected individuals with a history of breast cancer (Appendix Table 2, Copson et al. 2018. PubMed ID: 29337092; Table S3, Walsh et al. 2021. PubMed ID: 33479248). Functional studies suggest this variant does not substantially impact BRCA2 function (see Mesman. 2018. PubMed ID: 29988080). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972589-GA-G). In ClinVar, this variant is interpreted as uncertain and has been reviewed by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/96890/). Taken together, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 14, 2023

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

This sequence change creates a premature translational stop signal (p.Glu3316Asnfs*2) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs778530487, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 29337092, 33479248, 35264596, 36881271). This variant is also known as 9940delA (K3314fs) and c.9945del (p.Lys3315fs). ClinVar contains an entry for this variant (Variation ID: 96890). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect BRCA2 function (PMID: 29988080). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs431825381

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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