17-35101008-A-T

Position:

chr17-35101008-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000345365.11(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I311V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

RAD51D
ENST00000345365.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:8

Conservation

PhyloP100: 3.69

Variant links:

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 links:

RAD51L3-RFFL (HGNC:):

RAD51L3-RFFL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Benign=1, Uncertain_significance=8, Likely_benign=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/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.932T>A	p.Ile311Asn	missense_variant	10/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.655+193T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.932T>A	p.Ile311Asn	missense_variant	10/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000419

AC XY:

AN XY:

135922

show subpopulations

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.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727114

show subpopulations

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RAD51D: BP4, BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 17, 2024	BS1 -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2019	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 23, 2020	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	GeneKor MSA	Aug 01, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:2Benign:1

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	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 11, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

RAD51D-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 â€šÃ„ÃºWith Uncertain significance, other alleleâ€šÃ„Ã¹, 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

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 11, 2021

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Uncertain

0.67

D;D;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

.;D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.0076

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.9

L;L;.;.;.

MutationTaster

Benign

0.95

D;D;D;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over