Submissions for variant NM_000059.4(BRCA2):c.9613_9614delinsCT (p.Ala3205Leu)

dbSNP: rs276174926

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080951	SCV000073880	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129271	SCV000184031	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	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	2023-04-19	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, pancreatic, or prostate cancer (Malone et al., 2000; Maier et al., 2014; El Saghir et al., 2015; Abe et al., 2019; Santonocito et al., 2020; Zografos et al., 2022); Published functional studies demonstrate no damaging effect on splicing (Caux-Moncoutier et al., 2009; Sanz et al., 2010); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 9841_9842delinsCT; This variant is associated with the following publications: (PMID: 35753294, 25111659, 24728327, 10717622, 25777348, 20215541, 19471317, 25382762, 21120943, 31209999, 33471991, 34572941, 32438681, 30883245, 36011273)
Color Diagnostics, LLC DBA Color Health	RCV000129271	SCV000684078	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	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 detected in at least five individuals affected with breast cancer and two individuals affected with prostate cancer and at least two unaffected individuals (PMID: 10717622, 19471317, 20215541, 24728327, 25111659, 25777348, 30883245, 32438681, 33471991; Leiden Open Variation Database DB-ID BRCA2_002741, 35127508, 35402282). 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	2023-02-06	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 four 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, Patruno_2021, Zografos_2022, Bisgin_2022). These reports 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). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=1; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766658	SCV001133987	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000058 (2/34590 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 25777348 (2015), 10717622 (2000)), prostate cancer (PMID: 25111659 (2014)), and pancreatic cancer (PMID: 34034685 (2021)). It has also been reported in unaffected individuals (PMID: 33471991 (2021), 30883245 (2019), 24728327 (2014)). In addition, this variant was also reported to cause minimal exon 26 skipping in the BRCA2 gene (PMID: 20215541 (2010)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000766658	SCV002563167	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766658	SCV003830142	uncertain significance	not provided	2021-10-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000114136	SCV003932779	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	an indel in the BRCA2 gene (c.9613_9614delGCinsCT) which results in the substitution of Leucine for Alanine at amino acid position 3205. This mutation is considered as a variant of uncertain significance.
Baylor Genetics	RCV003460633	SCV004213581	uncertain significance	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003460633	SCV004543923	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
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, susceptibility to, 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
Department of Medical and Surgical Sciences, University of Bologna	RCV000114136	SCV004228304	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)