17-35107119-A-T

Position:

• chr17-35107119-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_002878.4(RAD51D):​c.349T>A​(p.Cys117Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,802 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 7.01

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_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.349T>A	p.Cys117Ser	missense_variant	5/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.349T>A	p.Cys117Ser	missense_variant	5/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.4-638T>A		intron_variant		2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

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: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 117 of the RAD51D protein (p.Cys117Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25186627, 26261251). ClinVar contains an entry for this variant (Variation ID: 184247). 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 with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces cysteine with serine at codon 117 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 been reported in individuals affected with breast cancer or ovarian cancer (PMID: 25186627, 26261251). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2024	The p.C117S variant (also known as c.349T>A), located in coding exon 5 of the RAD51D gene, results from a T to A substitution at nucleotide position 349. The cysteine at codon 117 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was detected in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This alteration has also been detected in 1/1781 individuals with a breast cancer diagnosis (Tung N. Cancer. 2015 Jan;121(1):25-33). In addition, this alteration was reported in 4/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 24, 2024

Variant summary: RAD51D c.349T>A (p.Cys117Ser) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.349T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Tung_2015, Song_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26261251, 25186627). ClinVar contains an entry for this variant (Variation ID: 184247). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2024

Observed in individuals with breast or ovarian cancer, but also seen in unaffected controls (PMID: 26261251, 25186627, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26261251, 25186627, 21111057, 14704354, 19327148, 33471991) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L;L;.;.
PROVEAN	Pathogenic	-7.6	D;.;.;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.83
MutPred		0.68		Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);.;.;
MVP		0.96
MPC		0.51
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs786201358; hg19: chr17-33434138;