Submissions for variant NM_007294.4(BRCA1):c.1745C>T (p.Thr582Met)

gnomAD frequency: 0.00001  dbSNP: rs786202386

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165167	SCV000215879	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	The p.T582M variant (also known as c.1745C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1745. The threonine at codon 582 is replaced by methionine, an amino acid with similar properties. This alteration has been identified a patient from a breast/ovarian cancer testing cohort in Korea (Ryu JM et al. Breast, 2017 Jun;33:109-116). In addition, this alteration was reported in 1/200 Italian individuals selected for genetic testing of BRCA1/2 according to NCCN guidelines (Doddato G et al. Front Oncol. 2021 May;11:649435). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000227464	SCV000289751	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-15	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000165167	SCV000821916	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764124	SCV000895097	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165167	SCV000909365	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 582 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast and/or ovarian cancer and an unaffected individual (PMID: 27376475, 28364669, 30725392, 33471991). This variant has been identified in 1/31360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001128034	SCV001287418	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001555644	SCV001777093	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer (Schenkel 2016, Ryu 2017, So 2019, Doddato 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 1864C>T; This variant is associated with the following publications: (PMID: 25011685, 31159747, 27376475, 26832770, 28364669, 31131967, 30725392, 15343273, 34026625)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165167	SCV003851067	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).