17-35101008-A-T

Variant names:

• chr17-35101008-A-T
• rs145309168
• NM_002878.4:c.932T>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002878.4(RAD51D):​c.932T>A​(p.Ile311Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,613,870 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:9
• Conservation: PhyloP100: 3.69

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075879693).
• BP6: Variant 17-35101008-A-T is Benign according to our data. Variant chr17-35101008-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127896.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=1, Uncertain_significance=7}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00023 (35/152296) while in subpopulation EAS AF= 0.00425 (22/5180). AF 95% confidence interval is 0.00287. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.932T>A	p.Ile311Asn	missense_variant	Exon 10 of 10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.932T>A	p.Ile311Asn	missense_variant	Exon 10 of 10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.426+193T>A		intron_variant	Intron 5 of 6	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 112 AN: 251488 Hom.: 1 AF XY: 0.000419 AC XY: 57 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00419

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1461574 Hom.: 2 Cov.: 30 AF XY: 0.000193 AC XY: 140 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00317

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000738

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

Jan 22, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD51D: BP4, BS1 -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 03, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22986143, 26824983, 32019284, 18951446, 28961279, 29263802, 29522266, 29338689, 30111881, 31159747, 31514334, 32255556, 32566746, 33785725, 32068069) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Jul 14, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 23, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:1 Benign:2

Oct 11, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RAD51D gene demonstrated a sequence change, c.932T>A, in exon 10 that results in an amino acid change, p.Ile311Asn. This sequence change has been described in the gnomAD database with a frequency of 0.43% in the East Asian sub-population (dbSNP rs145309168). The p.Ile311Asn change has been reported in individuals with ovarian, breast, and peritoneal cancers (PMIDs: 30111881, 26824983, 22986143). Additionally, two different amino acid changes at the same location, p.Ile311Val and p.Ile311Met, have been reported for predisposition to hereditary breast and ovarian cancer (PMID: 31159747). The p.Ile311Asn change affects a highly conserved amino acid residue located in a domain of the RAD51D protein that is not known to be functional. The p.Ile311Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile311Asn change remains unknown at this time. -

RAD51D-related disorder Uncertain:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51D c.932T>A variant is predicted to result in the amino acid substitution p.Ile311Asn. This variant has been reported in over 25 individuals with a personal or family history of breast and/or ovarian cancer (Lin et al. 2016. PubMed ID: 26824983; Table 2 Wong et al. 2016. PubMed ID: 29263802; Supp. Table 1 in Kwong et al. 2020. PubMed ID: 32068069; Hauke et al. 2018. PubMed ID: 29522266; Gervas et al. 2021. PubMed ID: 33785725; Table S5. Tsaousis et al. 2019. PubMed ID: 31159747). This variant has also been reported in individuals with a personal or family history of ovarian cancer (Table 2, Wickramanayake et al. 2012. PubMed ID: 22986143; Konstanta et al. 2018. PubMed ID: 301118810), an individual with gastric cancer (Tedaldi et al. 2019. PubMed ID: 31514334), and an individual with pancreatic ductal adenocarcinoma (Supp. Table 2 Cremin et al. 2020. PubMed ID: 32255556). This variant is reported in 0.43% of alleles in individuals of East Asian descent in gnomAD, including 1 homozygote. The c.932T>A variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127896/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51D p.Ile311Asn variant was identified in 6 of 1426 proband chromosomes (frequency: 0.0042) from individuals or families with breast and ovarian cancer (Lin 2016, Wickramanayake 2012, Wong 2016). The variant was also identified in dbSNP (ID: rs145309168) as “With Uncertain significance, other allele”, ClinVar (as likely benign by Invitae and as uncertain significance by GeneDx, Ambry Genetics and Counsyl), and Clinvitae databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 122 of 277230 chromosomes at a frequency of 0.00044 in the following populations: European (Non-Finnish) in 26 of 126716 chromosomes (freq. 0.0002), East Asian in 83 (1 homozygous) of 18868 chromosomes (freq. 0.004), European (Finnish) in 2 of 25794 chromosomes (freq. 0.00008) and South Asian in 9 of 30782 chromosomes (freq. 0.0003), and Other in 2 of 6468 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is located in the ATPase domain of the RAD51D protein (Kim 2011). The p.Ile311Asn residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Breast and/or ovarian cancer Benign:1

Jun 11, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Uncertain	0.67	D;D;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;L;.;.;.
PROVEAN	Uncertain	-2.9	D;.;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Benign	0.14	T;T;D;T;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.35
MVP		0.67
MPC		0.40
ClinPred		0.17	T
GERP RS		4.1
Varity_R		0.55
gMVP		0.80

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: rs145309168; hg19: chr17-33428027;