ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2006T>C (p.Met669Thr) (rs80356895)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130064 SCV000184891 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-17 criteria provided, single submitter clinical testing The p.M669T variant (also known as c.2006T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2006. The methionine at codon 669 is replaced by threonine, an amino acid with similar properties. This variant has been previously reported (designated as base change 2238thT>C based on NM_007300.3) in a Chinese patient with breast cancer (Sun L et al. Int J Clin Exp Pathol. 2014 Aug 15;7:6262-9). 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.
Counsyl RCV000031023 SCV000487917 uncertain significance Breast-ovarian cancer, familial 1 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000420884 SCV000518172 likely benign not specified 2018-01-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000130064 SCV000911034 likely benign Hereditary cancer-predisposing syndrome 2016-09-23 criteria provided, single submitter clinical testing
Mendelics RCV000031023 SCV001140587 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001472789 SCV001676927 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031023 SCV000053616 benign Breast-ovarian cancer, familial 1 2012-02-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031023 SCV000144273 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031023 SCV000591363 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Met669Thr variant was identified in 4 of 926 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer and was not identified in 60 control chromosomes from healthy individuals (Sun 2014). The variant was also identified in dbSNP (ID: rs80356895) as "With other allele" and ClinVar (classified as benign by SCRP; as likely benign by GeneDx; and as uncertain significance by Ambry Genetics, Counsyl, COGR and BIC). The variant was not identified in LOVD 3.0 or UMD-LSDB databases. The variant was identified in 12 of 276982 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 126578 chromosomes (freq: 0.000008) and East Asian in 11 of 18862 chromosomes (freq: 0.0006), but not in the African, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Met669 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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