Submissions for variant NM_007294.4(BRCA1):c.1874_1877dup (p.Val627fs)

dbSNP: rs80357516

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)	RCV000111711	SCV000299661	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167828	SCV000075628	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val627Serfs*4) 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 cancer and an individual affected with breast and/or ovarian cancer (PMID: 12505256, 22970155). This variant is also known as 1996insTAGT. ClinVar contains an entry for this variant (Variation ID: 54376). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000132134	SCV000187205	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-30	criteria provided, single submitter	clinical testing	The c.1874_1877dupTAGT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TAGT at nucleotide position 1874, causing a translational frameshift with a predicted alternate stop codon (p.V627Sfs*4). This alteration has been previously identified in individuals with early-onset breast cancer (Balz V et al. Cancer Genet. Cytogenet. 2002 Oct;138:120-7; Bellacosa A et al. Cancer Prev. Res. (Phila.) 2010 Jan;3:48-61). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration has been denoted as 1996insTAGT and 1997insTAGT in the published literature. 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111711	SCV000195895	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000047615	SCV000209880	pathogenic	not provided	2023-06-16	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; Observed in several individuals with personal and/or family histories consistent with hereditary breast and/or ovarian cancer (Balz et al., 2002; Thomassen et al., 2008; Bellacosa et al., 2010; Kwong et al., 2012); 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 1877_1878insTAGT, 1878_1879insTAGT, 1997insTAGT, and 1996insTAGT; This variant is associated with the following publications: (PMID: 21702907, 16267036, 18465347, 28888541, 12505256, 20051372, 27157322, 22970155, 33087929, 29446198)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047615	SCV000296276	pathogenic	not provided	2014-12-15	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111711	SCV000325162	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167828	SCV000698894	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1874_1877dupTAGT (p.Val627SerfsX4) 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. The variant was absent in 251314 control chromosomes. c.1874_1877dupTAGT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Balz_2002, Thomassen_2008, Kwong_2012, Couch_2015, Rebbeck_2018). 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. Six ClinVar submissions from clinical diagnostic laboratories and one expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000111711	SCV004216998	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132134	SCV004361045	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1877_1878insTAGT in the literature. 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 detected in at least four individuals affected with breast cancer (PMID: 12505256, 22970155, 25452441) and is detected in a breast cancer case-control meta-analysis in 2/60466 cases and absent in 53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001027). 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.
All of Us Research Program, National Institutes of Health	RCV000111711	SCV004818268	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1877_1878insTAGT in the literature. 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 detected in at least four individuals affected with breast cancer (PMID: 12505256, 22970155, 25452441) and is detected in a breast cancer case-control meta-analysis in 2/60464 cases and absent in 53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001027). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167828	SCV004847913	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Val627SerfsX4 variant in BRCA1 has been reported in at least 17 individuals with hereditary breast and/or ovarian cancer (HBOC; Kwong 2014, Balz 2002, Thomassen 2008, 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 627 and leads to a premature termination codon 4 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 Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 54376). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Department of Human Genetics, Hannover Medical School	RCV000111711	SCV005374870	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-10-17	criteria provided, single submitter	clinical testing	ClinGen BRCA1 VCEP: PVS1, PM5_Strong
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111711	SCV000144214	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000111711	SCV000211993	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167828	SCV000587165	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785208	SCV000923776	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000111711	SCV004244112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing