ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.303T>G (p.Tyr101Ter)

dbSNP: rs80356936
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112260 SCV000299438 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.
Invitae RCV000048054 SCV000076067 pathogenic Hereditary breast ovarian cancer syndrome 2023-07-17 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54758). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 17221156, 18679828, 26681312). This sequence change creates a premature translational stop signal (p.Tyr101*) 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).
GeneDx RCV000074578 SCV000108663 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.303T>G at the cDNA level and p.Tyr101Ter (Y101X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with hereditary breast and/or ovarian cancer, and has been found to be a recurrent variant in individuals of African ancestry (Russo 2007, Veschi 2007, Zhang 2009, Zhang 2012). We consider this variant to be pathogenic.
Ambry Genetics RCV000162861 SCV000213348 pathogenic Hereditary cancer-predisposing syndrome 2020-11-12 criteria provided, single submitter clinical testing The p.Y101* pathogenic mutation (also known as c.303T>G), located in coding exon 5 of the BRCA1 gene, results from a T to G substitution at nucleotide position 303. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This pathogenic mutation has been described as a Nigerian founder mutation in individuals of Yoruban ancestry (Zhang B et al. Fam. Cancer 2009; 8(1):15-22; Zhang J et al. Breast Cancer Res. Treat. 2012 Jul; 134(2):889-94; Fackenthal JD et al. Int. J. Cancer 2012 Sep; 131(5):1114-23). It has also been reported in multiple HBOC families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Veschi S et al. Ann. Oncol. 2007 Jun; 18 (Suppl 6):vi86-92; Russo A et al. Breast Cancer Res. Treat. 2007 Nov; 105(3):267-76). 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 RCV000112260 SCV000325542 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 RCV000048054 SCV000698998 pathogenic Hereditary breast ovarian cancer syndrome 2016-11-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.303T>G (p.Tyr101X) 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. p.Glu143X, p.Tyr261X). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120796 control chromosomes while it was reported in several breast cancer patients indicating causality. 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 RCV000162861 SCV001736585 pathogenic Hereditary cancer-predisposing syndrome 2020-08-17 criteria provided, single submitter clinical testing This variant replaces tyrosine with a translation stop signal at codon 101 of the BRCA1 protein. 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 over ten individuals affected with breast and/or ovarian cancer (PMID: 17221156, 17221156, 18679828, 22739995, 26681312, 31125277, 18679828). 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.
Baylor Genetics RCV000112260 SCV004215156 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-04-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112260 SCV000144982 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2007-01-18 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000048054 SCV000587045 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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