Submissions for variant NM_000059.4(BRCA2):c.4829_4830del (p.Val1610fs)

dbSNP: rs80359468

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077338	SCV000300790	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044500	SCV000072513	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1610Glyfs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs777265639, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16455195, 21559243, 21607582, 25476495). ClinVar contains an entry for this variant (Variation ID: 51721). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162922	SCV000213409	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.4829_4830delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4829 to 4830, causing a translational frameshift with a predicted alternate stop codon (p.V1610Gfs*4). This mutation has been reported in multiple breast and/or ovarian cancer families to date (Ahn SH et al. Cancer Lett. 2007 Jan 8;245(1-2):90-5; Faroog A et al. J. Oncol. 2011 Mar;2011:632870; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26), including multiple cohorts in Brazil (Alemar B et al. Cancer Genet. 2016 Sep;209(9):417-422; Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Cipriano NM et al. Breast Cancer. 2019 May;26:397-405). In one cohort of individuals undergoing BRCA1/2 testing at a commercial laboratory, approximately 40% of individuals with the c.4829_4830delTG mutation reported partial or full Ashkenazi Jewish ancestry (Rosenthal E et al. Breast Cancer Res. Treat. 2015 Jan;149(1):223-7), and in another study, this alteration was reported in both Ashkenazi and non-Ashkenazi Jewish breast cancer patients (Barnes-Kedar I et al. Breast Cancer Res. Treat. 2018 Nov;172:151-157). This alteration was reported in an individual diagnosed with pancreatic cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110:1067-1074). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 5057delTG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000217237	SCV000278852	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liede et al., 2002; Rashid et al., 2006; Ahn et al., 2007; Kim et al., 2012; Rosenthal et al., 2014; Kang et al., 2015; Alemar et al., 2016; Barnes-Kedar et al., 2018; Cipriano et al., 2018; Lowery et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5057_5058delTG or 5055_5056delTG; This variant is associated with the following publications: (PMID: 21607582, 12181777, 27425403, 16455195, 21559243, 16998791, 25476495, 22798144, 25863477, 26187060, 26687385, 22340495, 26295337, 29346284, 29506128, 30014164, 30787465, 34645131, 30535581, 29161300, 29922827, 28888541, 30720243, 29907814)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077338	SCV000327096	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162922	SCV000688899	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217237	SCV000887828	pathogenic	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 22798144 (2012), 21559243 (2011), 16455195 (2007), 30535581 (2019), 30720243 (2019), 30014164 (2018), 29907814 (2018), 29506128 (2018), 29446198 (2018), 29161300 (2017), and 25476495 (2015)). The frequency of this variant in the general population, 0.0001 (1/10048 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044500	SCV001338260	pathogenic	Hereditary breast ovarian cancer syndrome	2020-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4829_4830delTG (p.Val1610GlyfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250066 control chromosomes (gnomAD). c.4829_4830delTG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (examples- Liede_2002, Ahn_2007, Alemar_2017, Palmero_2018, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044500	SCV001365792	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-07	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
CeGaT Center for Human Genetics Tuebingen	RCV000217237	SCV003917273	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000044500	SCV004183369	pathogenic	Hereditary breast ovarian cancer syndrome	2020-02-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2
Baylor Genetics	RCV003473350	SCV004211810	pathogenic	Familial cancer of breast	2024-02-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077338	SCV004845736	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-09	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077338	SCV000109135	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077338	SCV000146489	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044500	SCV000587725	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research