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

dbSNP: rs80357373

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048698	SCV000076711	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-24	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	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000112427	SCV000489618	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-11-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000048698	SCV000839226	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112427	SCV000145214	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 1		no assertion provided	in vitro