ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.742A>C (p.Thr248Pro) (rs879255288)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238739 SCV000296440 uncertain significance Breast-ovarian cancer, familial 1 2016-03-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573207 SCV000661116 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing The p.T248P variant (also known as c.742A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 742. The threonine at codon 248 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well 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 RCV000238739 SCV000784961 uncertain significance Breast-ovarian cancer, familial 1 2017-02-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000573207 SCV000904895 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-17 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 248 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Invitae RCV000794112 SCV000933501 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-07-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 248 of the BRCA1 protein (p.Thr248Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 252390). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357655 SCV001553183 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr248Pro variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs879255288) as "With Uncertain significance allele", as well as the ClinVar and Clinvitae (1x, uncertain significance). The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Thr248 residue is not conserved in mammals and four out of five 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 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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