Submissions for variant NM_007294.4(BRCA1):c.824G>A (p.Gly275Asp)

gnomAD frequency: 0.00002  dbSNP: rs397509327

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000490300	SCV001161575	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00104 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086294	SCV000077172	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130114	SCV000184944	likely benign	Hereditary cancer-predisposing syndrome	2020-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000589691	SCV000210091	likely benign	not provided	2019-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19491284, 22116506, 29601120, 30702160, 32426482, 15235020, 24728327, 12624724, 14973102, 15168169, 27257965, 27383479, 27124784, 29770616, 30093976, 30415210, 30287823, 31481248, 28111427, 28364669, 25823446, 31348995)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240746	SCV000265882	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490300	SCV000267229	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000589691	SCV000337720	uncertain significance	not provided	2015-11-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120298	SCV000538457	uncertain significance	not specified	2016-12-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 4 papers in HGMD, that include affected and unaffected individuals. This variant is classified in ClinVar with 2 stars as VUS by Invitae, Ambry, GeneDx, and West China Hospital. The variant has a Max MAF of 0.13% in ExAC (12 East Asian alleles) and 0.1% in gnomAD (20 alleles). 19 non-mammals have an Asp at this position.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120298	SCV000699315	benign	not specified	2020-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.824G>A (p.Gly275Asp) 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 0.00022 in 298510 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.001 (in the gnomAD database and in Momozawa_2018). This frequency is comparable to the expected maximum frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001 vs 0.001), suggesting the variant could be a benign polymorphism found in populations from East Asia. In addition, the variant was reported in some East Asian subpopulations with even higher allele frequencies, e.g. in Koreans (0.0026, in gnomAD), and in Japanese (0.0012, in HGVD), further supporting a benign role for the variant. c.824G>A has been reported in the literature numerous individuals (generally in East Asians) affected with breast- and ovarian cancer and other tumor phenotypes (Carney_2010, Haffty_2009, Judkins_2005, Kato_2016, Kawahara_2004, Sakayori_2003, Shin_2016, Suter_2004, Zhong_2016, Bhaskaran_2019, Chan_2018, Choi_2018, Lee_2018, Park_2017), but was also found in several unaffected East Asian controls (Park_2017, Momozawa_2018). At-least two co-occurrences with another likely pathogenic variant (BRCA1 c.5165C>T, p.Ser1722Phe; Chan_2018) and a pathogenic variant (BRCA2 c.2808_2811delACAA, p.Ala938Profs, internal testing observation) have been observed, providing supporting evidence for a benign role. Two recent case-control association studies, involving breast cancer patients and controls of Korean- (Park_2017) and Japanese ancestry (Momozawa 2018), found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of these studies classified that the variant as likely benign/benign, respectively. In addition, in a study involving Korean breast cancer patients, multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology) and predicted this variant to be likely benign (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven other clinical diagnostic laboratories and one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (n=5), benign (n=1, ENIGMA) and VUS (n=6). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any actionable evidence supporting causality in over 15 years of review and co-occurrence with other pathogenic variants in the BRCA1/2 genes, further supported by an expert panel assessment as outlined above, the variant was re-classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000130114	SCV000910845	likely benign	Hereditary cancer-predisposing syndrome	2015-11-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589691	SCV001133654	likely benign	not provided	2018-08-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000490300	SCV001140618	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490300	SCV001280985	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000130114	SCV002537925	likely benign	Hereditary cancer-predisposing syndrome	2020-12-14	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496722	SCV002811405	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-10-31	criteria provided, single submitter	clinical testing
ITMI	RCV000120298	SCV000084450	not provided	not specified	2013-09-19	no assertion provided	reference population
Center for Precision Medicine, Meizhou People's Hospital	RCV002250549	SCV002520905	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only