Submissions for variant NM_000059.4(BRCA2):c.7977-4_7977-3del

dbSNP: rs876659992

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220776	SCV000277029	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The c.7977-4_7977-3delTT intronic variant, located in intron 16 of the BRCA2 gene, results from a deletion of two nucleotides within intron 16 of the BRCA2 gene. These nucleotide positions are well conserved in available vertebrate species. This variant, designated as c.7976-5_7976-4delTT, has been reported in an individual diagnosed with breast cancer at age 38 whose family history included both breast and ovarian cancers (Chen X et al. Hum. Mutat. 2006 May;27:427-35). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Although this alteration did not have any effect on splicing impact in one study, data were not shown (Chen X et al. Hum. Mutat. 2006 May;27:427-35). Internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The splice defect is similar to that observed in several close match alterations at the same acceptor site including c.7977-6T>G (Fraile-Bethencourt E et al. PLoS Genet., 2017 Mar;13:e1006691). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692708	SCV000820546	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with personal and family history of breast cancer and/or ovarian cancer (PMID: 16619214). ClinVar contains an entry for this variant (Variation ID: 232794). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 16619214; internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759666	SCV000889146	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194388	SCV001363896	uncertain significance	not specified	2019-09-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7977-4_7977-3delTT alters a 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. Chen_2006 reports this variant has no effect on splicing process. The variant was absent in 248894 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7977-4_7977-3delTT, has been reported in the literature in one proband whose family history of breast and/or ovarian cancer (Chen_2006). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6216delC , p.Leu2073TyrfsX8), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291602	SCV002584708	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-10-06	criteria provided, single submitter	clinical testing	The BRCA2 c.7977-4_7977-3del intronic change results from the deletion of two non-conserved nucleotides at position 7944-4 to 7944-3 of intron 17 of the BRCA2 gene. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. RNA sequencing studies are not in agreement about the splicing effect of this variant (PMID: 16619214). This variant has been reported in an individual with a personal history of breast cancer and a family history of breast and ovarian cancer (PMID: 16619214). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000759666	SCV003917275	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, BP4
All of Us Research Program, National Institutes of Health	RCV004804910	SCV005425779	uncertain significance	BRCA2-related cancer predisposition	2024-02-22	criteria provided, single submitter	clinical testing	This variant causes a deletion of two nucleotides at the -4 and -3 position in intron 17 of the BRCA2 gene. An RNA study using carrier-derived RNA found this variant did not impact splicing (PMID: 16619214). This variant has been reported in individuals affected with early-onset breast cancer, with a family history of breast and ovarian cancer (PMID: 16619214). 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.