Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.303T>G(p.Tyr101Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y101Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43104260-A-C is Pathogenic according to our data. Variant chr17-43104260-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 54758.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104260-A-C is described in Lovd as [Pathogenic]. Variant chr17-43104260-A-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Sep 08, 2016
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jan 18, 2007
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Dec 31, 2023
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jul 17, 2023
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). -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Nov 14, 2016
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. -
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 17, 2020
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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Nov 01, 2017
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. -