Submissions for variant NM_007294.4(BRCA1):c.5152+20T>A

gnomAD frequency: 0.00009  dbSNP: rs376836050

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119141	SCV000153856	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000123931	SCV000167318	benign	not specified	2014-05-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000130822	SCV000185718	likely benign	Hereditary cancer-predisposing syndrome	2013-12-05	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	RCV000411645	SCV000487762	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130822	SCV000683260	benign	Hereditary cancer-predisposing syndrome	2015-10-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123931	SCV000918724	benign	not specified	2019-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5152+20T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 250844 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00016 vs 0.001), allowing no conclusion about variant significance. c.5152+20T>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Wagner_1999), however in one case the variant was present in both an affected and unaffected family member, which provides supporting evidence for a benign role of this variant, although the age of the family members was not provided (Mohammadi_2009). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.7235insG via UMD; BRCA1 c.68_69delAG from an internal specimen; and BRCA1 c.5152+2T>G from an internal specimen), providing supporting evidence for a benign role. Additionally, the variant has been reported in our lab in a patient as homozygous. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as a benign variant.
Mendelics	RCV000411645	SCV001140485	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123931	SCV005090333	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689666	SCV001905997	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123931	SCV001973823	benign	not specified		no assertion criteria provided	clinical testing