ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4935G>C (p.Arg1645Ser) (rs80357373)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048698 SCV000076711 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000656790 SCV000210188 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4935G>C at the cDNA level, p.Arg1645Ser (R1645S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant, also known as BRCA1 c.5054G>C by alternate nomenclature, has been observed in individuals with breast and/or ovarian cancer (Pal 2005, Haffty 2009, Ruiz 2014, Nakamura 2015). BRCA1 Arg1645Ser was not observed in large population cohorts (Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1645Ser is located in the BRCT1 domain and a region known to interact with multiple other proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Arg1645Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000167324 SCV000218174 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing The p.R1645S variant (also known as c.4935G>C), located in coding exon 14 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4935. The arginine at codon 1645 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history of breast and/or ovarian cancer (Pal T et al. Cancer, 2005 Dec;104:2807-16; Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9; Ruiz A et al. Biomed Res. Int. 2014 Jun;2014:542541; Nakamura S et al. Breast Cancer 2015 Sep;22:462-8; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Momozawa Y et al. Nat. Commun. 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000112427 SCV000489618 uncertain significance Breast-ovarian cancer, familial 1 2016-11-03 criteria provided, single submitter clinical testing
Mendelics RCV000048698 SCV000839226 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000167324 SCV000903889 likely benign Hereditary cancer-predisposing syndrome 2016-05-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656790 SCV001133599 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing
Mendelics RCV000112427 SCV001140503 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112427 SCV000145214 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235133 SCV000591548 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg1645Ser variant was identified in 3 of 1332 proband chromosomes (frequency: 0.002) from individuals or families with Ovarian and Breast cancers (Haffty 2009, Pal 2005, Ruiz 2014). The variant was also identified in dbSNP (ID: rs80357373 “With Uncertain significance allele”. This variant was not identified in the Exome Variant Server project and Exome Aggregation Consortium (ExAC-released March 14, 2016) databases. The p.Arg1645Ser variant was identified in the Clinvar database and was classified as variant of uncertain significance by Ambry Genetics, GeneDx and BIC; Invitae did not provide a classification. The BIC database identified the variant 1X with unknown clinical importance. The p.Arg1645 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant amino acid Serine (Ser) is present in African clawed frog, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Brotman Baty Institute,University of Washington RCV000112427 SCV001243838 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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