Submissions for variant NM_000059.4(BRCA2):c.574_575del (p.Met192fs)

dbSNP: rs80359533

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031574	SCV000282414	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044741	SCV000072754	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met192Valfs*13) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12960223, 26681312). This variant is also known as 800delAT and 802delAT. ClinVar contains an entry for this variant (Variation ID: 37993). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131852	SCV000186405	pathogenic	Hereditary cancer-predisposing syndrome	2013-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131852	SCV000186907	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	The c.574_575delAT pathogenic mutation, located in coding exon 6 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 574 to 575, causing a translational frameshift with a predicted alternate stop codon (p.M192Vfs*13). This alteration (also designated 800delAT and 802delAT) has been identified in multiple breast, ovarian, and pancreatic cancer patients (Lalloo F et al. Lancet. 2003 Mar;361:1101-2; Evans DG et al. J. Med. Genet. 2003 Sep;40:e107; Sanz DJ et al. Clin Cancer Res. 2010 Mar;16:1957-67; Litton J et al. Cancer. 2012 Jan;118:321-5; Walker EJ et al. Fam Cancer. 2019 04;18:241-251; Nones K et al. Ann Oncol. 2019 07;30:1071-1079). 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	RCV000235138	SCV000210703	pathogenic	not provided	2023-08-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: failed to rescue susceptibility to DNA damaging agents (Stauffer et al., 2020); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 802delAT and 800delAT, 802_803delAT; This variant is associated with the following publications: (PMID: 12960223, 23983145, 20215541, 16644204, 24131973, 17899372, 26295337, 24094589, 21913181, 31090900, 26681312, 12672316, 30267352, 33758026, 28888541, 30787465, 32393813)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031574	SCV000267733	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235138	SCV000296730	pathogenic	not provided	2020-09-10	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 cancer (PMIDs: 12960223 (2003), 21913181 (2012), 31090900 (2019)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031574	SCV000327274	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031574	SCV000489153	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131852	SCV000683730	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 800delAT in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 12672316, 21913181, 24094589, 24131973, 26681312, 31090900). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044741	SCV000694898	pathogenic	Hereditary breast ovarian cancer syndrome	2016-01-22	criteria provided, single submitter	clinical testing	Variant summary: This c.574_575delAT variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 192 and leads to a premature termination codon 12 amino acids downstream. It is predicted to cause a truncated or absent BRCA2 protein. Heterozygous loss-of-function due to mutations in this gene is an established disease mechanism in HBOC. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Asp252fs). This variant was not found in approximately 121394 chromosomes from the broad and large populations from ExAC. This variant has been reported in many HBOC patients/families from literature and databases. Multiple clinical laboratories and reputable databases have classified this variant as pathogenic. Taken together, this variant has currently been classified as a Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235138	SCV002049627	pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	The BRCA2 c.574_575delAT; p.Met192ValfsTer13 variant (rs80359533), also known as 800delAT and 802_803delAT, has been described in the literature in individuals and families with breast and ovarian cancer (Evans 2003, Susswein 2016). The variant is listed in the ClinVar database (Variation ID: 37993) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Evans DG et al. Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. J Med Genet. 2003 Sep;40(9):e107. PMID: 12960223. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312.
Fulgent Genetics, Fulgent Genetics	RCV005003417	SCV002811137	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-03-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473193	SCV004211859	pathogenic	Familial cancer of breast	2024-03-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235138	SCV004225731	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
All of Us Research Program, National Institutes of Health	RCV000031574	SCV004846790	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-09	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 800delAT in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 12672316, 21913181, 24094589, 24131973, 26681312, 31090900). This variant has not been identified 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)	RCV000031574	SCV000054180	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-07-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031574	SCV000147183	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	RCV000044741	SCV000587556	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355820	SCV001550815	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Met192ValfsX13 variant was identified in 3 of 2638 proband chromosomes (frequency: 0.0011) from individuals or families with hereditary breast and ovarian cancer (Evans 2003, Litton 2011, Safra 2013). The variant was also identified in dbSNP (ID: rs587782398) with no classification, ClinVar (11x as pathogenic, reviewed by expert panel), LOVD 3.0 (3x), UMD-LSDB (9x as causal), BIC Database (30x as pathogenic), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Met192ValfsX13 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 192 and leads to a premature stop codon at position 204. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.