Submissions for variant NM_007294.4(BRCA1):c.2564A>C (p.Gln855Pro)

gnomAD frequency: 0.00001  dbSNP: rs768001441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165754	SCV000216498	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	The p.Q855P variant (also known as c.2564A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2564. The glutamine at codon 855 is replaced by proline, an amino acid with similar properties. This alteration was identified in individuals pursuing BRCA1/2 analysis in Japan (Nakamura S et al. Breast Cancer, 2015 Sep;22:462-8; Arai M et al. J Hum Genet, 2018 Apr;63:447-457). This variant has also been identified in breast cancer cohorts as well as unaffected control groups across studies (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000165754	SCV000683047	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 855 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and ovarian cancer family and in two individuals affected with breast cancer, in which one of the breast cancer affected individual also has a deleterious BRCA2 mutation (PMID: 11802209, 24249303, 29176636). This variant has been detected in two Japanese breast cancer and prostate cancer case-control studies in 3/7051 female breast cancer cases and 3/11241 unaffected individuals and 3/7636 prostate cancer cases and 5/12366 unaffected individuals (PMID: 30287823, 31214711). This variant also has been detected in a breast cancer case-control meta-analysis and a pancreatic cancer case-control study in which this variant was absent in 60466 breast cancer cases and 1005 pancreatic cancer cases and present in 1/53461 and 8/23705 unaffected individuals in the two respectively studies (PMID: 32980694, 33471991). This variant has not been identified 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.
Invitae	RCV000637567	SCV000759031	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758797	SCV000887644	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506725	SCV000918714	uncertain significance	not specified	2020-09-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2564A>C (p.Gln855Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 298848 control chromosomes (gnomAD and publications), predominantly at a frequency of 1.7e-04 within 47462 Japanese controls who were 60 years old or over and did not have past history nor family history of cancers (Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2564A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Meindl 2002, Nakamura 2015, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic BRCA2 variant has been reported (Nakamura_2015; co-occurring variant not specified), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of Likely Benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-segregation with disease, breast tumor pathology and bioinformatic predictions; however, no specific data was provided for independent assessment. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of clinical and/or functional importance becomes available.
GeneDx	RCV000758797	SCV001824004	uncertain significance	not provided	2020-12-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2683A>C; This variant is associated with the following publications: (PMID: 30287823, 33087888, 29176636, 31131967, 20305393, 24359602, 11802209, 24249303)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165754	SCV003847575	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).