Submissions for variant NM_000059.4(BRCA2):c.4933_4935del (p.Lys1645del)

dbSNP: rs80359472

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800614	SCV000296560	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000041 (1/243486 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer who also carried a pathogenic BRCA1 truncating variant (PMID: 27553368 (2016)). The variant has also been reported in an individual with ovarian cancer (PMID: 32850417 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547263	SCV000635414	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This variant, c.4933_4935del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Lys1645del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761871715, gnomAD 0.003%). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 27553368, 32850417). ClinVar contains an entry for this variant (Variation ID: 252422). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics	RCV000563234	SCV000661260	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The c.4933_4935delAAA variant (also known as p.K1645del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame AAA deletion at nucleotide positions 4933 to 4935. This results in the in-frame deletion of a lysine at codon 1645. In one study, this variant was detected in 1/80 Portuguese breast and/or ovarian cancer patients who were tested for BRCA1/2 mutations and who did not carry a founder mutation (Pinto P et al. Breast Cancer Res. Treat., 2016 Sep;159:245-56). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000563234	SCV000911397	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 amino acid, lysine 1645, from the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with early-onset breast cancer, who also carried a pathogenic truncation variant in the BRCA1 gene (PMID:27553368). This variant has been identified in 1/243486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778819	SCV002015001	uncertain significance	not specified	2022-07-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4933_4935delAAA (p.Lys1645del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 243486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4933_4935delAAA has been reported in the literature in one individual affected with Breast Cancer (Pinto_2016), however this individual also carried a co-occurring pathogenic variant (BRCA1 c.3817C>T (p.Gln1273Ter)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000563234	SCV002533912	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998940	SCV004845750	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 amino acid, lysine 1645, from the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with early-onset breast cancer, who also carried a pathogenic truncation variant in the BRCA1 gene (PMID:27553368). This variant has been identified in 1/243486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000547263	SCV005045372	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-16	criteria provided, single submitter	clinical testing