rs772306012

Positions:

• chr17-35119611-C-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002878.4(RAD51D):​c.2dupT​(p.Met1fs) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 frameshift, start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.88

Genes affected

RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

ENSG00000267618 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35119611-C-CA is Pathogenic according to our data. Variant chr17-35119611-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480547.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.2dupT	p.Met1fs	frameshift_variant, start_lost	1/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.2dupT	p.Met1fs	frameshift_variant, start_lost	1/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.3+1679dupT		intron_variant		2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246580 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.000156 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2022	The c.2dupT pathogenic mutation (also known as p.M1?) is located in coding exon 1 of the RAD51D gene and results from a duplication of T at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Although this alteration is expected to disrupt the translation initiation site, the RAD51D gene contains a second in frame methionine at amino acid position 16. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first 15 amino acids from the protein. Based on structural analysis, the first 15 amino acids are predicted to play an important role in protein function (Kim YM et al. Int. J. Biochem. Cell Biol., 2011 Mar;43:416-22). While this exact alteration has not been reported in the literature, similar alterations impacting the initiation codon (c.1A>T and c.1A>G) have been detected in individuals with breast or ovarian cancer (Gutiérrez-Enríquez S et al. Int. J. Cancer, 2014 May;134:2088-97; Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2023	This variant results in the loss of translation initiator codon of the RAD51D gene. Although functional studies have not been reported, this variant is expected to result in an absent or non-functional protein product. It has been shown that the highly conserved RAD51D N-terminus (a.a. 1-83) encodes the single-stranded DNA binding domain and that the 13-residue N-terminal tail (a.a. 1-13) contributes to proper protein folding via hydrophobic interactions between side chains of the N-terminal tail and alpha helices of the single-stranded DNA binding domain (PMID: 21111057). These findings suggest that the production of a full-length protein from p.Met1 is important for RAD51 function. While an in-frame methionine occurs at codon 16, it is not known if it can serve as an alternative translation initiation site to produce a functional RAD51D protein. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, different variants that also disrupt p.Met1 (c.1A>G and c.1A>T) have been reported in individuals affected with ovarian cancer (ClinVar variation ID: 127884 and 419798). This variant has been identified in 1/246458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Nov 13, 2023	ACMG criteria used to clasify this variant: PS1_MOD, PM1, PS4_SUP, PM2_SUP, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 23, 2023	This sequence change affects the initiator methionine of the RAD51D mRNA. The next in-frame methionine is located at codon 16. This variant is present in population databases (rs772306012, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24130102, 26681312). ClinVar contains an entry for this variant (Variation ID: 480547). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772306012; hg19: chr17-33446630;