Submissions for variant NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro)

dbSNP: rs80357252

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049206	SCV000077219	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000218097	SCV000277412	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.A322P variant (also known as c.964G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 964. The alanine at codon 322 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a patient with renal cell carcinoma, and a functional comparison showed that this alteration displayed 82% homology-directed repair (HDR) function in comparison to wild type BRCA1 (Lu C et al. Nat Commun 2015; 6:10086). This alteration was identified in an individual diagnosed with cancer who had next generation sequencing performed (Huang KL et al. Cell, 2018 04;173:355-370.e14). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000483940	SCV000566751	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: partial loss of homology-directed repair activity (Lu et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and renal cell carcinoma (Lu et al., 2015; Abulkhair et al., 2018; Huang et al., 2018); Also known as 1083G>C; This variant is associated with the following publications: (PMID: 15385441, 16518693, 15235020, 16267036, 30199306, 31911673, 31853058, 32377563, 20215511, 15343273, 9926942, 9582019, 11521194, 29884841, 33087888, 31131967, 26689913, 29684080, 29625052, 27720647)
Color Diagnostics, LLC DBA Color Health	RCV000218097	SCV000903583	likely benign	Hereditary cancer-predisposing syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780997	SCV000918742	likely benign	not specified	2022-09-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.964G>C (p.Ala322Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.964G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Mu_2016, Abulkhair_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was reported to have a non-significant decrease in HDR activity compared to wild-type (Lu_2015). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483940	SCV001133659	likely benign	not provided	2022-12-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000218097	SCV002527131	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218097	SCV003846265	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000083228	SCV000115302	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083228	SCV000143967	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing