Submissions for variant NM_002878.4(RAD51D):c.577-2A>G

dbSNP: rs1555567649

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567818	SCV000667145	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The c.577-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 7 in the RAD51D gene. This alteration has been previously identified in a German patient diagnosed with triple negative breast cancer at age 52, with no family history of breast or ovarian cancer, who also screened negative for mutations in 13 additional genes associated with breast and/or ovarian cancer susceptibility, including BRCA1 and BRCA2 (Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). This variant was also detected in 2/6178 families with a history of tubo-ovarian carcinoma or breast cancer (Yang X et al. J Natl Cancer Inst, 2020 12;112:1242-1250). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Internal and published RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Bueno-Martínez E et al. Cancers (Basel), 2021 Jun;13). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760066	SCV000889828	pathogenic	not provided	2024-08-15	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal RAD51D mRNA splicing. In the published literature, this variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 27616075 (2016), 29255180 (2017), 30257646 (2018), 32107557 (2020), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). In addition, this variant alters RAD51D RNA splicing in a minigene assay (PMID: 34200360 (2021)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041429	SCV001205046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-08-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the RAD51D 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 RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27616075, 30257646, 32107557). ClinVar contains an entry for this variant (Variation ID: 482184). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 34200360). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000567818	SCV001353496	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-08	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 6 of the RAD51D gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with breast cancer (PMID: 27616075, 30257646). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192467	SCV001360604	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-07-05	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.577-2A>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 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250980 control chromosomes. c.577-2A>G has been reported in the literature in at-least two individuals affected with Triple Negative Hereditary Breast and Ovarian Cancer (Golmard_2017, Kraus_2017, Hoyer_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001041429	SCV004200422	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2023-03-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001041429	SCV004932977	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-04	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
GeneDx	RCV000760066	SCV005373329	likely pathogenic	not provided	2024-04-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele and demonstrated to result in multiple aberrant transcripts in a minigene assay in a gene for which loss of function is a known mechanism of disease (PMID: 34200360); Observed in association with breast cancer (PMID: 32107557, 27616075); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26556299, 27616075, 29255180, 34200360, 32107557, 30257646)