Submissions for variant NM_007294.4(BRCA1):c.4258C>T (p.Gln1420Ter)

dbSNP: rs80357305

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077569	SCV000300098	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	RCV000236776	SCV000292522	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Thirthagiri 2008, Minucci 2015, Couch 2015); 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 4377C>T; This variant is associated with the following publications: (PMID: 9796975, 25452441, 25525159, 18627636, 26306726, 29446198, 32341426, 28993434, 30702160)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236776	SCV000296323	pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast or ovarian cancer in the published literature (PMIDs: 18627636 (2008) and 26306726 (2015)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077569	SCV000325908	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000077569	SCV000693534	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Glutamine to a Termination codon at amino acid residue 1420 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. This variant is also known as c.4377C>T in the literature has been reported in patients with breast and/or ovarian cancer (PMID: 18627636, 26306726). The mutation database ClinVar contains entries for this variant (Variation ID: 55155).
Mendelics	RCV000496798	SCV000839238	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022156	SCV001183856	pathogenic	Hereditary cancer-predisposing syndrome	2025-03-08	criteria provided, single submitter	clinical testing	The p.Q1420* pathogenic mutation (also known as c.4258C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4258. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Thirthagiri E et al. Breast Cancer Res. 2008 Jul;10:R59; Minucci A et al. Expert Rev. Mol. Diagn. 2015 Aug;15:1383-403; Wen WX et al. J Med Genet, 2018 02;55:97-103; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Dorling et al. N Engl J Med. 2021 02;384:428-439). Note, this variant is also referred to as 4377C>T in the literature. 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.
Institute of Genomics, University of Tartu	RCV000077569	SCV001430698	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496798	SCV001587923	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1420*) 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/or ovarian cancer (PMID: 18627636, 21120943, 26306726). This variant is also known as c.4377C>T. ClinVar contains an entry for this variant (Variation ID: 55155). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001022156	SCV001736419	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 18627636, 26306726; doi:10.1515/tjb.2019.0424). 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.
Sema4, Sema4	RCV001022156	SCV002538279	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Baylor Genetics	RCV000077569	SCV004216993	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496798	SCV005885330	pathogenic	Hereditary breast ovarian cancer syndrome	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4258C>T (p.Gln1420X) 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. The variant was absent in 251466 control chromosomes. c.4258C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Berchuck_1998, Caux-Moncoutier_2011, Concolino_2014, Thirthagiri_2008). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21120943, 18627636, 24578176, 9796975, 24670361). ClinVar contains an entry for this variant (Variation ID: 55155). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077569	SCV000109371	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-04-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077569	SCV000145043	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-22	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496798	SCV000587385	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077569	SCV002588809	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing