Submissions for variant NM_000059.4(BRCA2):c.4964dup (p.Tyr1655Ter)

dbSNP: rs398122789

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077738	SCV000300807	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	RCV000218684	SCV000273734	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-26	criteria provided, single submitter	clinical testing	The c.4964dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4964, causing a translational frameshift with a predicted alternate stop codon (p.Y1655*). This variant was reported in multiple individuals with features consistent with BRCA2-related hereditary breast and ovarian cancer syndrome (Peixoto A et al. Clin Genet, 2015 Jul;88:41-8; Peixoto A et al. Front Oncol, 2020 Jul;10:1318;Palmero EI et al. Sci Rep, 2018 06;8:9188). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480916	SCV000296733	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152220 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and/or families with hereditary breast and/or ovarian cancer (PMID: 24916970 (2015), 29907814 (2018)), and in individuals with high grade serous ovarian cancer (PMID: 32850417 (2020)). In a large breast cancer association study, this variant was reported in an individual with breast cancer (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). 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	RCV000077738	SCV000327113	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480916	SCV000568470	pathogenic	not provided	2016-03-30	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted BRCA2 c.4964dupA at the cDNA level and p.Tyr1655Ter (Y1655X) at the protein level. The normal sequence, with the base that is duplicated in braces, is TGTT[A]CACA. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4964dupA, also denoted BRCA2 5192dupA using alternate nomenclature, has been reported in association with hereditary breast /ovarian cancer (Peixoto 2014). This variant is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557404	SCV000635415	pathogenic	Hereditary breast ovarian cancer syndrome	2024-06-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 ovarian cancer (PMID: 21709188, 27836010, 28724667, 29487695). ClinVar contains an entry for this variant (Variation ID: 91830). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000557404	SCV001360792	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4964dupA (p.Tyr1655X) 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 240078 control chromosomes. c.4964dupA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Peixoto_2014; Palmero_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474670	SCV004212882	pathogenic	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077738	SCV000109541	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-12-01	no assertion criteria provided	clinical testing