Submissions for variant NM_000059.4(BRCA2):c.610del (p.Ser205fs)

dbSNP: rs80359560

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113877	SCV000300339	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.
Ambry Genetics	RCV000164920	SCV000215608	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	The c.610delC pathogenic mutation, located in coding exon 6 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 610, causing a translational frameshift with a predicted alternate stop codon (p.S205Vfs*6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation (designated as 838delC) has been identified in a woman with contralateral breast cancer, in which her primary breast cancer was diagnosed under the age of 54 (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113877	SCV000327356	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164920	SCV001355363	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 7 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 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390407	SCV001592132	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser205Valfs*6) 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 contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 52015). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001839876	SCV002099566	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Frameshift variant demonstrated to result in multiple isoforms that are predicted to undergo protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Stauffer 2020); Observed in an individual with breast cancer (Borg 2010); 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 838delC; This variant is associated with the following publications: (PMID: 23983145, 20104584, 32393813)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001390407	SCV003934809	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.610delC (p.Ser205ValfsX6) 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. The variant was absent in 251368 control chromosomes (gnomAD). c.610delC has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Borg_2010). Experimental evidence from one publication has shown that alternative splicing of BRCA2 can restore the ORF, specifically when the variant of interest is found on a transcript missing exon 5, which typically results in a frameshift (Stauffer_2020). Since this ORF restoration necessitates the splicing of a typically degraded transcript, this result does not allow convincing conclusions about the variants effect on the risk of developing breast cancer. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 29446198, 32393813). Six ClinVar submitters, including one expert panel (ENIGMA), have assessed the variant since 2014: all six classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001839876	SCV005624485	pathogenic	not provided	2024-09-07	criteria provided, single submitter	clinical testing	The BRCA2 c.610del (p.Ser205Valfs*6) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an individual with breast cancer (PMID: 20104584 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113877	SCV000147284	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502900	SCV000591696	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser205ValfsX6 variant was identified in 1 of 4206 proband chromosomes (frequency: 0.000) from individuals with breast cancer in a population based sample study (Borg, 2006). The variant was identified in dbSNP (ID: rs80359560) “With pathogenic allele”. It was also identified in HGMD, the BIC database (1X as pathogenic) and the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) 2x (1X from BIC as a pathogenic variant, and 1X by Invitae, classification not provided). The deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 205 and leads to a premature stop codon 6 codons downstream. 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.