BRCA1 NM_007294.3:c.4159T>C, Ser1387Pro

The p.S1387P variant (also known as c.4159T>C), located in coding exon 10 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4159. The serine at codon 1387 is replaced by proline, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was also identified in a cohort of Chinese patients at high risk to have hereditary breast and ovarian cancer predisposition (Shao D et al. Cancer Sci. 2020 Feb;111:647-657), as well as in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789). Another study reported that this variant was not found in 7636 unselected prostate cancer patients, but was present at an allele frequency of 0.00016 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst. 2020 Apr;112(4):369-376). Additionally, this alteration is located at a BRCA1 residue phosphorylated by ATM, which is required for induction of the S-phase checkpoint in response to DNA damage (Goldstein M et al. Cancer Res. 2015 Jul;75:2699-707; Xu B et al. Cancer Res. 2002 Aug;62:4588-91). However, one functional study reported that this alteration had similar levels of homology-directed repair activity to wild-type, and also had similar levels of colony formation to wild-type in the presence of cisplatin and olaparib (Foo TK et al. Cancer Res. 2021 Sep;81(18):4676-4684). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces serine with proline at codon 1387 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer and in four unaffected individuals (PMID: 27257965, 30287823). This variant also has been reported in a prostate cancer and a pancreatic cancer case-control study in which it was only detected in unaffected individuals (PMID: 31214711, 32980694). This variant has been identified in 1/248290 chromosomes 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.

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This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1387 of the BRCA1 protein (p.Ser1387Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27257965, 30287823, 30702160). ClinVar contains an entry for this variant (Variation ID: 224433). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 34301763). 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.