Submissions for variant NM_007294.4(BRCA1):c.143del (p.Met48fs)

dbSNP: rs80357637

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)	RCV000030993	SCV000299413	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	RCV000047475	SCV000075488	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met48Serfs*2) 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 ovarian cancer (PMID: 26023681). This variant is also known as 262delT. ClinVar contains an entry for this variant (Variation ID: 37412). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129404	SCV000184173	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	The c.143delT pathogenic mutation, located in coding exon 3 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 143, causing a translational frameshift with a predicted alternate stop codon (p.M48Sfs*2). This mutation has been reported in several patients with ovarian cancer (Spearman AD et al. J. Clin. Oncol., 2008 Nov;26:5393-400; Foley SB et al. EBioMedicine, 2015 Jan;2:74-81; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488). This alteration was also reported in 2/50726 patients from an unselected population cohort from a single health system who underwent exome sequencing (Manickam K et al. JAMA Netw Open, 2018 09;1:e182140). 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	RCV000030993	SCV000325070	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047475	SCV000605747	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-15	criteria provided, single submitter	clinical testing	The p.Met48fs variant in BRCA1 has been reported in at least 6 individuals with BRCA1-associated cancers (Foley 2015, Breast Cancer Information Core (BIC) datab ase) 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 48 and leads to a premature termination codon 2 amino acids downstream. Heterozygous loss of function of the BRCA1 gene is an established disease mecha nism in individuals with hereditary breast and ovarian cancer (HBOC). Additional ly, the p.Met48fs variant was classified as Pathogenic on September 8, 2016 by t he ClinGen-approved ENIGMA expert panel (ClinVar SCV000299413.2). In summary, th is variant meets our criteria to be classified as pathogenic for HBOC in an auto somal dominant manner.
GeneDx	RCV000657256	SCV000778986	pathogenic	not provided	2022-12-22	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 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 BRCA1 262delT; Observed in individuals with ovarian cancer (Dworkin et al., 2009; Carter et al., 2018); This variant is associated with the following publications: (PMID: 28152038, 16267036, 18824701, 26023681, 30787465, 31409081, 32741062, 19340607, 30322717)
Color Diagnostics, LLC DBA Color Health	RCV000129404	SCV000911646	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 1882470, 26023681, 30322717). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047475	SCV000918698	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.143delT (p.Met48SerfsX2) 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 250126 control chromosomes (gnomAD). c.143delT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (examples: Judkins 2005, Spearman 2008, Foley 2014). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657256	SCV001133487	pathogenic	not provided	2023-05-01	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 ovarian cancer (PMID: 30322717 (2018), 26023681 (2015)). The variant has also been described in a world-wide study of BRCA1 and BRCA2 mutations carriers (PMID: 29446198 (2018)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV000030993	SCV004216976	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030993	SCV000053585	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030993	SCV000144462	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	RCV000047475	SCV000587020	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research