ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4631C>T (p.Pro1544Leu) (rs80356917)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132132 SCV000187202 uncertain significance Hereditary cancer-predisposing syndrome 2014-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000479934 SCV000564743 uncertain significance not provided 2014-10-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4631C>T at the cDNA level, p.Pro1544Leu (P1544L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant has been reported once in the Breast Cancer Information Core (BIC) database and is listed as having unknown clinical significance (Judkins 2005). BRCA1 Pro1544Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro1544Leu occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Pro1544Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780989 SCV000918721 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4631C>T (p.Pro1544Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. One functional study demonstrated that the variant protein has a stronger transcriptional activity than the wild type with a classification of "likely not pathogenic (Woods 2016). The variant was absent in 121380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4631C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins 2005). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A recent study classifies this variant as likely not pathogenic based on their multifactorial likelihood analysis (Thompson 2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112368 SCV000145134 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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