ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3835G>A (p.Ala1279Thr) (rs80357036)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082264 SCV000076361 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129501 SCV000184273 likely benign Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000435150 SCV000526552 likely benign not specified 2016-10-25 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000435150 SCV000605854 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679693 SCV000806941 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129501 SCV000902917 benign Hereditary cancer-predisposing syndrome 2017-04-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083198 SCV000115272 benign Breast-ovarian cancer, familial 1 2012-03-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083198 SCV000144890 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 RCV001357948 SCV001553561 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ala1279Thr variant was not identified in the literature nor was it identified in the GeneInsight-COGR, COSMIC, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80357036) as “With Uncertain significance, other allele”, ClinVar and Clinvitae (3x classified as uncertain significance by Invitae, Quest Diagnostics and BIC; 2x classified as likely benign by Ambry Genetics and GeneDx; 1x classified as benign by SCRP), LOVD 3.0 (5 entries classified as effect unknown or not classified), UMD-LSDB (2 entries, classification neutral, 1 entry with a co-occurring pathogenic variant), BIC Database (1 entry, clinical importance unknown) databases. The variant was identified in control databases in 4 of 245878 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 4 of 111354 chromosomes (freq: 0.000036), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ala1279Thr residue is not conserved in mammals; indeed a threonine residue is observed in Gorilla gorilla at this position. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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