Submissions for variant NM_000059.4(BRCA2):c.9945del (p.Glu3316fs)

dbSNP: rs431825381

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083011	SCV000301421	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-05	reviewed by expert panel	curation	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).
GeneDx	RCV000160314	SCV000210805	uncertain significance	not provided	2020-11-06	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000165269	SCV000215986	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204290	SCV000259466	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000165269	SCV000906828	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-21	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000083011	SCV001139280	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193143	SCV001361803	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	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. 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). ClinVar contains an entry for this variant (Variation ID: 96890). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004528778	SCV004110154	uncertain significance	BRCA2-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003460763	SCV004213672	uncertain significance	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160314	SCV004220678	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193143	SCV005090079	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083011	SCV000115085	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing