Submissions for variant NM_007294.4(BRCA1):c.4410A>T (p.Glu1470Asp)

gnomAD frequency: 0.00016  dbSNP: rs80357075

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724288	SCV000108679	likely benign	not provided	2021-03-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30400234, 15385441, 24728327, 20104584, 22682623, 16267036, 27843123, 28781887, 23704879, 21520273)
Ambry Genetics	RCV000131557	SCV000186560	benign	Hereditary cancer-predisposing syndrome	2015-03-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000724288	SCV000225889	uncertain significance	not provided	2016-01-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083415	SCV000254987	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131557	SCV000688501	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120257	SCV000699148	likely benign	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4410A>T (p.Glu1470Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251242 control chromosomes, predominantly at a frequency of 8.7e-05 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4410A>T has been reported in the literature in individuals with a personal and/or family history of breast/ovarian cancers (example, Judkins_2005, Borg_2010, Dutil_2012, Diaz-Zabala_2018, Matta_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with the same pathogenic variant have been reported in 3 separate individuals (BRCA2 c.3922G>T, p.Glu1308X; NHGRI BIC and internal testing), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (example, Woods_2016, Fernandes_2019, Nepomuceno_2022). The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 20104584, 21520273, 30400234, 22682623, 30765603, 27843123, 16267036, 36329109, 36171434, 30212499, 28781887). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=6; Benign, n=1; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724288	SCV001133584	likely benign	not provided	2023-05-23	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001083415	SCV002515212	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131557	SCV002537750	likely benign	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724288	SCV004565236	likely benign	not provided	2023-07-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001083415	SCV005045474	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-22	criteria provided, single submitter	clinical testing
ITMI	RCV000120257	SCV000084409	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077572	SCV000109375	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077572	SCV000145087	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing