ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9613_9614delinsCT (p.Ala3205Leu) (rs276174926)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080951 SCV000073880 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129271 SCV000184031 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-10 criteria provided, single submitter clinical testing ​The c.9613_9614delGCinsCT variant (also known as p.A3205L), located in coding exon 25 of the BRCA2 gene, results from the deletion of two nucleotides (GC) and the insertion of two nucleotides (CT) at nucleotide positions 9613 to 9614. The alanine at codon 3205 is replaced by leucine, an amino acid with similar properties. This variant has been reported in individuals with hereditary breast, ovarian, and/or prostate cancer, but its clinical significance has been reported as uncertain in several studies (Malone KE et al. Cancer. 2000 Mar 15;88:1393-402; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Maier C et al. Prostate. 2014 Oct;74:1444-51; El Saghir NS et al. Oncologist. 2015 Apr;20:357-64; Abe T et al. J. Clin. Oncol., 2019 05;37:1070-1080; Santonocito C et al. Cancers (Basel), 2020 May;12). In an ancestrally diverse cohort of 681 healthy individuals who underwent genome sequencing, this variant was detected in 1/331 Europeans (Bodian DL et al. PLoS One. 2014 Apr 11;9:e94554). A RT-PCR splicing assay showed that this alteration did not show a remarkable splicing consequence, producing only minimal skipping of coding exon 25 (Sanz DJ et al. Clin. Cancer Res. 2010 Mar 15;16:1957-67). Of note, this alteration is also designated as 9841GC/CT and 9841_9842GC>CT in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral 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.
GeneDx RCV000766658 SCV000210801 uncertain significance not provided 2020-02-07 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history including breast and prostate cancer (Malone 2000, Maier 2014, El Saghir 2015); Published functional studies demonstrate no damaging effect on splicing (Caux-Moncoutier 2009, Sanz 2010); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25111659, 24728327, 10717622, 25777348, 20215541, 19471317, 25382762, 21120943, 31209999)
Color Health, Inc RCV000129271 SCV000684078 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces alanine with leucine at codon 3205 of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 10717622, 19471317, 20215541, 25777348) and pancreatic cancer (PMID 25111659), as well as in a healthy control individual (PMID: 24728327). This variant has been identified in 6/251370 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 RCV000120371 SCV000916855 likely benign not specified 2021-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9613_9614delinsCT (p.Ala3205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9613_9614delinsCT has been reported in the literature in individuals affected with a variety of cancers such as breast, ovarian, prostate and/or pancreatic surveillance (example, Sanz_2010, Maier_2014, Malone_2000, El Seghir_2015, Abe_2019, Santonocito_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (CDH1 c.382delC, p.His128Ilefs; BRCA1 c.2475delC, p.Asp825fsX21), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no damaging effect of this variant on splicing in patient lymphocytes (Sanz_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=1; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766658 SCV001133987 uncertain significance not provided 2020-03-17 criteria provided, single submitter clinical testing
ITMI RCV000120371 SCV000084523 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000114136 SCV000147677 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353477 SCV000592297 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Ala3205Leu variant was identified by Malone (2000) in a study of young women diagnosed with breast cancer, and was also identified in HGMD, in UMD (1X as an unclassified variant), and in the BIC database (6X with unknown clinical importance). The p.Ala3205 residue in not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; however, this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735632 SCV000863770 uncertain significance Breast and/or ovarian cancer 2013-05-03 no assertion criteria provided clinical testing

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