Submissions for variant NM_000059.4(BRCA2):c.635_636del (p.Arg212fs)

dbSNP: rs80359575

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000076962	SCV000300340	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000076962	SCV000327399	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000483149	SCV000568451	pathogenic	not provided	2020-01-22	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 personal and family history consistent with pathogenic variants in this gene (Verhoog 1999, Meindl 2002, Castera 2014, Meisel 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 863_864delGA, 862delAG, or 634_635delAG; This variant is associated with the following publications: (PMID: 24549055, 28324225, 10550133, 11802209, 16683254, 21305653, 32719484)
Ambry Genetics	RCV000510046	SCV000607925	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The c.635_636delGA pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 635 to 636, causing a translational frameshift with a predicted alternate stop codon (p.R212Kfs*2). This mutation has been reported in three Czech families suspected to have hereditary breast and/or ovarian cancer (Machackova E et al. Klin Onkol. 2019;32:51-71). 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.
Color Diagnostics, LLC DBA Color Health	RCV000510046	SCV000688977	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 8 of the BRCA2 protein, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 10550133, 11802209) and has been identified in 13 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 0/53461 controls (p-value=0.253) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001437). 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000076962	SCV000744389	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483149	SCV000887873	pathogenic	not provided	2017-12-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000076962	SCV001428524	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387343	SCV001587950	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg212Lysfs*2) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as 862delAG, and c.634_635delAG. ClinVar contains an entry for this variant (Variation ID: 91445). For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000483149	SCV002010340	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001387343	SCV002051155	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.635_636delGA (p.Arg212LysfsX2) 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 was absent in 244212 control chromosomes. c.635_636delGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Machackova_2019, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=9, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV001762200	SCV002580483	pathogenic	Familial cancer of breast	2021-09-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000483149	SCV003812575	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000483149	SCV004024553	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PP4;PM2;PVS1
Baylor Genetics	RCV001762200	SCV004212868	pathogenic	Familial cancer of breast	2021-12-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076962	SCV000108759	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-12-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000076962	SCV000147358	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000076962	SCV000733215	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000483149	SCV001955930	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000483149	SCV002036326	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000076962	SCV004243981	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing