Submissions for variant NM_000059.4(BRCA2):c.1861_1863delinsAGC (p.Glu621Ser)

dbSNP: rs2072424315

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001070355	SCV001235578	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-22	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 863399). This missense change has been observed in individual(s) with breast cancer (PMID: 25777348). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 621 of the BRCA2 protein (p.Glu621Ser).
Color Diagnostics, LLC DBA Color Health	RCV001184693	SCV001350729	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with serine at codon 621 of the BRCA2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
GeneDx	RCV001576954	SCV001804246	uncertain significance	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this variant does not alter protein structure/function; Observed in an individual with breast cancer (El Saghir 2015); Also known as c.2089_2091delGAAinsAGC; This variant is associated with the following publications: (PMID: 25777348)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824921	SCV002074254	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1861_1863delinsAGC (p.Glu621Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 240264 control chromosomes. c.1861_1863delinsAGC has been reported in the literature in at least one individual affected with Breast Cancer (El Saghir_2015). This individual was found to carry a second variant in BRCA1 c.1772C>T [p.Ile591THr] which is classified as VUS/likely benign in ClinVar (54345). These data on variant occurences in the general population and in reported patients do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001184693	SCV003847507	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).