ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4485-8C>T (rs397507234)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229987 SCV000289802 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000031180 SCV000488101 uncertain significance Breast-ovarian cancer, familial 1 2015-12-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508687 SCV000605879 uncertain significance not specified 2017-07-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000584536 SCV000688503 likely benign Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508687 SCV000916826 uncertain significance not specified 2021-06-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4485-8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4485-8C>T has been reported in the literature in affected individuals without strong evidence for or against pathogenicity (Lu_2012, Flower_2015 ). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001358004 SCV001886851 benign not provided 2015-07-23 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031180 SCV000053780 likely benign Breast-ovarian cancer, familial 1 2011-08-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358004 SCV001553627 uncertain significance not provided no assertion criteria provided clinical testing The BRCA1 c.4485-8C>T variant was identified in 1 of 300 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (Flower 2015). The variant was also identified in the following databases: dbSNP (ID: rs397507234) as "With other allele", ClinVar (2x uncertain significance, 3x likely benign), Clinvitae, Cosmic (1x, confirmed somatic, in carcinoma of the ovary), and LOVD 3.0 (1x). The variant was classified as a likely benign variant by the Sharing Clinical Reports Project (SCRP, derived from Myriad reports). The variant was not identified in the following databases: COGR, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 2 of 276702 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 2 of 126368 chromosomes (freq: 0.00002); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. This variant was classified as “likely non-pathogenic or of little clinical significance” based on the methylation profile in a breast tumour sample (Flower 2015). The c.4485-8C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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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