Submissions for variant NM_000059.4(BRCA2):c.8331+2T>G

dbSNP: rs398122602

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217152	SCV000274163	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-11	criteria provided, single submitter	clinical testing	The c.8331+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 17 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Several variants at this splice donor site demonstrated substantial but incomplete abnormal splicing in multiple different RNA analyses (Ambry internal data; Gelli E et al. Cancers (Basel), 2019 Mar;11; Nix P et al. Fam Cancer, 2021 Jan; Fraile-Bethencourt E et al. PLoS Genet, 2017 Mar;13:e1006691). Furthermore, the close match alteration BRCA2 c.8331+2T>C was observed in individuals who collectively do not present with a clinical history seen in typical high-risk hereditary breast and ovarian cancer (HBOC) variant carriers (Nix P et al. Fam Cancer, 2021 Jan;). However, these data cannot rule out the possibility of a hypomorphic variant with atypical risks. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215392	SCV001387132	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.8331+2T nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 19619314, 21614564, 24504028, 25186627, 28008555, 28339459, 29339979, 29446198, 29487695). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 230571). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change affects a donor splice site in intron 18 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001215392	SCV002600843	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8331+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247808 control chromosomes (gnomAD). c.8331+2T>G has been reported in the literature in at least one individual affected with ovarian cancer (Lilyquist_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004760445	SCV005369613	likely pathogenic	not provided	2024-03-29	criteria provided, single submitter	clinical testing	Observed in a patient with ovarian cancer (PMID: 28888541); A different nucleotide change at the same canonical splice site (c.8331+2T>C) has demonstrated aberrant splicing, resulting in both null and wildtype transcripts (PMID: 28339459, 30832263, 31143303, 32123317); Canonical splice site variant predicted to result in a null allele; although, in the absence of functional evidence the actual effect of this sequence changes is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8559+2T>G; This variant is associated with the following publications: (PMID: 28888541, 28339459, 30832263, 31143303, 32123317)