Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Evidence- |
RCV000241007 | SCV000299540 | 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. |
| Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000241007 | SCV000324957 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000509759 | SCV000608101 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-16 | criteria provided, single submitter | clinical testing | The p.W372* pathogenic mutation (also known as c.1115G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1115. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Additionally, this alteration was identified in the homozygous state in two sisters with features of Fanconi Anemia including developmental delay, microcephaly and abnormal skin pigmentation (Seo A et al. Proc Natl Acad Sci U S A, 2018 05;115:5241-5246). This alteration was also identified in an individual diagnosed with breast cancer from China (Deng M et al. Int J Cancer, 2019 09;145:1517-1528). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001328427 | SCV001519550 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-03-14 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.1115G>A (p.Trp372X) 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 allele was found at a frequency of 4e-06 in 251174 control chromosomes. c.1115G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). One clinical diagnostic laboratory, an expert panel (ENIGMA), a consotrium (CIMBA) and a database (OMIM) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV001328427 | SCV001583988 | pathogenic | Hereditary breast ovarian cancer syndrome | 2019-04-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). A different variant (c.1116G>A) giving rise to the same protein effect observed here (p.Trp372*) has been determined to be pathogenic (PMID: 9333265, 11504767, 16515586, 16683254, 26848529). This suggests that this variant is also likely to be causative of disease. This variant has been observed to be heterozygous in several individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 28831036, 29907814, 29446198, 29625052). In addition, this variant has been observed to be homozygous in two siblings with clinical features consistent with Fanconi anemia (PMID: 29712865). ClinVar contains an entry for this variant (Variation ID: 54134). This variant is present in population databases (rs397508838, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Trp372*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. |
| OMIM | RCV000767397 | SCV000898012 | pathogenic | Fanconi anemia, complementation group S | 2019-04-17 | no assertion criteria provided | literature only |