17-35107376-C-G

Variant names:

• chr17-35107376-C-G
• rs587782848
• NM_002878.4:c.335G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002878.4(RAD51D):​c.335G>C​(p.Gly112Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G112D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.55
• Publications: 1 publications found

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]

RAD51D Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 17-35107376-C-G is Pathogenic according to our data. Variant chr17-35107376-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234081.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.335G>C	p.Gly112Ala	missense_variant	Exon 4 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.335G>C	p.Gly112Ala	missense_variant	Exon 4 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.4-895G>C		intron_variant	Intron 1 of 6	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403932 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701156

African (AFR) AF: 0.00 AC: 0 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 85080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059400

Other (OTH) AF: 0.00 AC: 0 AN: 58492

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 02, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G112A variant (also known as c.335G>C), located in coding exon 4 of the RAD51D gene, results from a G to C substitution at nucleotide position 335. The glycine at codon 112 is replaced by alanine, an amino acid with similar properties. This alteration was shown to have reduced repair of DNA interstrand crosslinks and also reduced interactions with DNA repair binding partners RAD51C and XRCC2 (Gruver AM et al. Mutagenesis 2005 Nov; 20(6):433-40). In addition, internal structural analysis predicts that this alteration causes destabilization of a critical functional motif leading to loss or impairment of ATPase function (Walker J et al. EMBO J. 1982; 1(8):945-51). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Apr 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this variant affects RAD51D protein function (PMID: 16236763). This sequence change replaces glycine with alanine at codon 112 of the RAD51D protein (p.Gly112Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 234081). 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 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H;.;.
PhyloP100		5.5
PROVEAN	Pathogenic	-5.1	D;.;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.93
MutPred		0.87		Loss of glycosylation at S111 (P = 0.0534);Loss of glycosylation at S111 (P = 0.0534);.;.;
MVP		0.99
MPC		0.47
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.83
Mutation Taster		=25/75	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587782848; hg19: chr17-33434395;