Submissions for variant NM_000059.4(BRCA2):c.6466_6469del (p.Ser2156fs)

dbSNP: rs80359596

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241080	SCV000301055	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.
GeneKor MSA	RCV000238933	SCV000296827	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes four bases from exon 11 of the BRCA2 mRNA (c.6466_6469delTCTC), causing a frameshift after codon 2156 and the creation of a premature translation stop signal 11 amino acid residues later, p.(Ser2156Asnfs*11). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID:252446).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241080	SCV000327436	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571815	SCV000666164	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The c.6466_6469delTCTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6466 to 6469, causing a translational frameshift with a predicted alternate stop codon (p.S2156Nfs*11). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496329	SCV000759003	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser2156Asnfs*11) 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 present in population databases (rs748536459, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with personal or family histories of breast and/or ovarian cancer (PMID: 28724667, 29310832, 29752822, 30702160). This variant is also known as c.6462_6465del (p.Y2154fs). ClinVar contains an entry for this variant (Variation ID: 252446). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268916	SCV001448170	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001268916	SCV001449789	pathogenic	not provided	2014-10-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001268916	SCV003819831	likely pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796129	SCV005415789	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		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496329	SCV000587850	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354002	SCV000592054	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn2135LysfsX3 deletion variant has been reported in the literature in 6/4516 proband chromosomes of individuals with invasive epithelial ovarian carcinoma and prostate cancer; although no control chromosomes were tested to establish the variants frequency in the general population (Zhang 2011; Kote-Jarai 2011). In the latter reference, one patient had a family history of breast cancer [sister, mother, aunt], as well as incidences of other malignancies such as cancer of the pancreas, leukemia, skin and gliomas. The second patient with prostate cancer from the same study had 2 incidences of bowel cancer in his family (Kote-Jarai 2011). The variant has been reported in the UMD (x28), HGMD as well as BIC database (x13) as a variant of clinical importance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80359584) but no frequency information was provided therefore not very informative for assessing the population frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2135 and leads to a premature stop codon, 3 codons downstream. This alteration is then predicted to lead to 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. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735586	SCV000863724	pathogenic	Breast and/or ovarian cancer	2012-07-06	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000241080	SCV004243719	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing