Submissions for variant NM_007294.4(BRCA1):c.4574_4575del (p.Gln1525fs)

dbSNP: rs80357813

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077576	SCV000282330	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048595	SCV000076608	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1525Argfs*5) 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 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: 9523200, 22333603, 24728189). This variant is also known as 4693delAA. ClinVar contains an entry for this variant (Variation ID: 55229). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077576	SCV000267712	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216673	SCV000274048	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	clinical testing	The c.4574_4575delAA pathogenic mutation, located in coding exon 13 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4574 to 4575, causing a translational frameshift with a predicted alternate stop codon (p.Q1525Rfs*5). This alteration has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Greenman J et al. Genes Chromosomes Cancer. 1998 Mar;21(3):244-9; Robertson L et al. Br. J. Cancer, 2012 Mar;106:1234-8; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Copson ER et al. Lancet Oncol, 2018 02;19:169-180; McVeigh TP et al. Eur. J. Cancer, 2018 May;95:20-29). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077576	SCV000326001	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508650	SCV000605884	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 9523200 (1998),11183185 (2000), 22333603 (2012), 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA1)) and in individuals with ovarian cancer (PMID: 24728189 (2014), 29614442 (2018)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048595	SCV000918706	pathogenic	Hereditary breast ovarian cancer syndrome	2017-09-05	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4574_4575delAA (p.Gln1525ArgfsX5) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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.4603G>T, p.Glu1535X; c.4655_4658delACTT, p.Tyr1552fsX6; c.4689C>G, p.Tyr1563X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 124462 control chromosomes from ExAC and literature. The variant was reported in the literature in individuals affected by breast or ovarian cancer (Robertson 2012, Song 2014, Greenman 1998, Fong 2009, Morgan 2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000216673	SCV001348224	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 of the BRCA1 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 been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11183185, 19329713, 19553641, 20127978, 22333603, 29337092). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508650	SCV001449935	pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508650	SCV001471753	pathogenic	not provided	2020-02-27	criteria provided, single submitter	clinical testing	The BRCA1 c.4574_4575delAA; p.Gln1525ArgfsTer5 variant (rs80357813), also known as 4693delAA, is reported in the literature in individuals with breast or ovarian cancer (Ellis 2000, Greenman 1998, Morgan 2010, Robertson 2012, Song 2014) and is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 55229). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Ellis D et al. Low prevalence of germline BRCA1 mutations in early onset breast cancer without a family history. J Med Genet. 2000 Oct;37(10):792-4. Greenman J et al. Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer. Genes Chromosomes Cancer. 1998 Mar;21(3):244-9. Morgan JE et al. Genetic diagnosis of familial breast cancer using clonal sequencing. Hum Mutat. 2010 Apr;31(4):484-91. Robertson L et al. BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer. 2012 Mar 13;106(6):1234-8. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048595	SCV004847909	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Gln1525ArgfsX5 variant in BRCA1 has been reported in at least 15 individuals with hereditary breast and/or ovarian cancer (HBOC; Greenman 1998, Ellis 2000, Al-Mulla 2009, Song 2014, Robertson 2012, BIC database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1525 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55229). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
GeneDx	RCV000508650	SCV005201801	pathogenic	not provided	2024-02-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; 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 4693_4694del; This variant is associated with the following publications: (PMID: 33087929, 20104584, 20127978, 34326862, 36169650, 34657373, 19553641, 29337092, 11183185, 9523200, 16267036, 19329713, 20700108, 22333603, 29614442, 34981296, 37736432, 33471991, 24728189)
Sharing Clinical Reports Project (SCRP)	RCV000077576	SCV000109379	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-05-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077576	SCV000145120	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048595	SCV000587408	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001271025	SCV001451839	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000508650	SCV001552300	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Gln1525Argfs*5 variant was identified in 23 of 64496 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Rebbeck 2018, Robertson 2012, Song 2014). The variant was also identified in dbSNP (ID: rs80357813) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and eight other submitters), LOVD 3.0 (6x as pathogenic), and in UMD-LSDB (5x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.4574_4575del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1525 and leads to a premature stop codon at position 1529. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 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.
PreventionGenetics, part of Exact Sciences	RCV004554680	SCV004800492	pathogenic	BRCA1-related disorder	2024-03-01	no assertion criteria provided	clinical testing	The BRCA1 c.4574_4575delAA variant is predicted to result in a frameshift and premature protein termination (p.Gln1525Argfs*5). This variant has been reported to be causative for hereditary breast and ovarian cancer syndrome (HBOC) (see for example, reported as 4693delAA at Greenman et al. 1998. PubMed ID: 9523200; Table S1 of Frugtniet et al. 2022. PubMed ID: 34657373). Loss of function variants up and downstream of this position have been reported to be causative for HBOC (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.