Submissions for variant NM_007294.4(BRCA1):c.2767_2770del (p.Val923fs)

dbSNP: rs80357661

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)	RCV000083190	SCV000299833	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000497271	SCV000210026	pathogenic	not provided	2014-05-09	criteria provided, single submitter	clinical testing	This deletion of 4 nucleotides is denoted BRCA1 c.2767_2770delGTTA at the cDNA level and p.Val923IlefsX76 (V923IfsX76) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GACA[GTTA]ATAT. The deletion causes a frameshift, which changes a Valine to an Isoleucine at codon 923, and creates a premature stop codon at position 76 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider This variant, also known as c.2886_2889delGTTA using alternate nomenclature, to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000083190	SCV000296419	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564043	SCV000668381	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-15	criteria provided, single submitter	clinical testing	The c.2767_2770delGTTA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2767 to 2770, causing a translational frameshift with a predicted alternate stop codon (p.V923Ifs*76). This alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53) and in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589720	SCV000698977	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2767_2770delGTTA (p.Val923IlefsX76) 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 (e.g. c.2806_2809delGATA (p.Asp936fsX63), c.2864C>A (p.Ser955X), and c.2868delT (p.Gln957fsX43)). The variant allele was found at a frequency of 4.1e-06 in 245770 control chromosomes (gnomAD). c.2767_2770delGTTA has been reported in the literature in individuals affected with tumors that belong to the Hereditary Breast and Ovarian Cancer (HBOC) syndrome tumor spectrum (Pritchard 2016, Susswein 2015, and in the BIC database). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000589720	SCV002184313	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val923Ilefs*76) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357661, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54678). This premature translational stop signal has been observed in individual(s) with prostate cancer or endometrial cancer (PMID: 26681312, 27433846).
Sharing Clinical Reports Project (SCRP)	RCV000083190	SCV000115264	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083190	SCV000144542	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162404	SCV002758473	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research