ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3902G>A (p.Ser1301Asn) (rs1057519496)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586928 SCV000565779 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3902G>A at the cDNA level, p.Ser1301Asn (S1301N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). Using alternate nomenclature, this variant would be defined as BRCA1 4021G>A. BRCA1 Ser1301Asn has been observed as a somatically acquired variant in a case of breast cancer (Nik-Zainal 2016). BRCA1 Ser1301Asn was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1301Asn occurs at a position where amino acids with properties similar to serine are tolerated across species and is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser1301Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509773 SCV000608207 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000416523 SCV000635929 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1301 of the BRCA1 protein (p.Ser1301Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. 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: 375449). 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 asparagine 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.
Integrated Genetics/Laboratory Corporation of America RCV000586928 SCV000699084 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3902G>A (p.Ser1301Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121388 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586928 SCV001133571 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing
Color RCV000509773 SCV001348245 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing

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