ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5071A>G (p.Thr1691Ala) (rs397509219)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589379 SCV000292911 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5071A>G at the cDNA level, p.Thr1691Ala (T1691A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant, also known as BRCA1 5190A>G using alternate nomenclature, was reported to be associated with RNA similar to wild type in a study of splicing defects using stimulated lymphocytes (Houdayer 2012). BRCA1 Thr1691Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1691Ala occurs at a position that is conserved in mammals and is located within the BRCT1 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr1691Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573049 SCV000665875 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000573049 SCV000683246 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589379 SCV000699197 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5071A>G (p.Thr1691Ala) variant involves the alteration of a conserved nucleotide located in BRCT domain. p.Thr1691Ala was predicted to destabilize the BRCT domain and could have a functional impact (Caputo_2012). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 3/5 splice prediction tools predict no significant impact on normal splicing, which was confirmed by RNA analysis in patient's T lymphoctes (Houdayer_2012). This variant is absent in 121146 control chromosomes. This variant has been reported in patients in literature or databases without convincing evidence supporting pathogenicity of this variant. Taken together, this variant is classified as VUS until more information is available.
Counsyl RCV000662496 SCV000785015 uncertain significance Breast-ovarian cancer, familial 1 2017-03-23 criteria provided, single submitter clinical testing

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