chr17-35118568-C-A

Position:

• chr17-35118568-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002878.4(RAD51D):​c.196G>T​(p.Val66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.00400

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]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057495058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.196G>T	p.Val66Leu	missense_variant	3/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1	n.232+2723G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.196G>T	p.Val66Leu	missense_variant	3/10	1	NM_002878.4	ENSP00000338790	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2021	This missense variant replaces valine with leucine at codon 66 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2015

This variant is denoted RAD51D c.196G>T at the cDNA level, p.Val66Leu (V66L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Val66Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. RAD51D Val66Leu occurs at a position that is not conserved and is located in the N-terminal linker domain and within the region that preferentially binds ssDNA (Kim 2011, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51D Val66Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 66 of the RAD51D protein (p.Val66Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 419663). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.4
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.18	N;N;.
MutationTaster	Benign	1.0	D;D;D;N;N;N;N
PROVEAN	Benign	0.040	N;N;.
REVEL	Benign	0.048
Sift	Benign	0.83	T;T;.
Sift4G	Benign	0.49	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.16
MutPred		0.51		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.39
ClinPred		0.17	T
GERP RS		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56026142; hg19: chr17-33445587;