Submissions for variant NM_007298.3(BRCA1):c.787+1824_787+1825delinsGT (rs1064793056)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480523	SCV000564729	uncertain significance	not specified	2014-10-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2611_2612delCCinsGT at the cDNA level, p.Pro871Val (P871V) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is TGCT[delCCinsGT]GTTT. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Proline to a Valine (CCG>GTG). This variant has not, to our knowledge, been published in the literature as either a mutation or benign polymorhism. BRCA1 Pro871Val 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 Valine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro871Val occurs at a position that is highly variable across species and is located in the DNA-binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, we consider BRCA1 Pro871Val to be a variant of uncertain significance.
Invitae	RCV000821444	SCV000962200	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline with valine at codon 871 of the BRCA1 protein (p.Pro871Val). The proline residue is weakly conserved and there is a small physicochemical difference between proline and valine. 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: 418068). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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