Submissions for variant NM_000059.4(BRCA2):c.9748dup (p.Ser3250fs)

dbSNP: rs886040850

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256608	SCV000324791	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	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	RCV000256608	SCV000328167	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771233	SCV000903332	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 27 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 Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819235	SCV000959883	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser3250Phefs*5) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acid(s) of the BRCA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 24010542). This variant is also known as 9976insT. ClinVar contains an entry for this variant (Variation ID: 267171). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000771233	SCV002693419	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	The c.9748dupT pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of T at nucleotide position 9748, causing a translational frameshift with a predicted alternate stop codon (p.S3250Ffs*5). This alteration occurs at the 3' terminus of theBRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 169 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region includes the RAD51 binding domain. This mutation has been reported in a Greek woman with early onset, triple negative breast cancer who had a family history of breast cancer; this individual was also found to have a gross deletion in BRCA1 (Konstantopoulou I et al. Clin Genet, 2014 Jan;85:36-42; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Fostira F et al. J Med Genet, 2020 01;57:53-61). Of note, this variant is also designated as c.9748_9749insT and 9976insT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003463729	SCV004214588	pathogenic	Familial cancer of breast	2021-04-03	criteria provided, single submitter	clinical testing