17-35107055-T-C

Position:

chr17-35107055-T-C

Variant summary

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

The ENST00000345365.11(RAD51D):c.413A>G(p.Asn138Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. N138H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

RAD51D
ENST00000345365.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: -0.0660

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=0.03353533).

BP6

Variant 17-35107055-T-C is Benign according to our data. Variant chr17-35107055-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127889.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8}. Variant chr17-35107055-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000256 (39/152248) while in subpopulation AMR AF= 0.00177 (27/15290). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.413A>G	p.Asn138Ser	missense_variant	5/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.233-574A>G		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.413A>G	p.Asn138Ser	missense_variant	5/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251474

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.0000746

AC:

109

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000256

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2023	The RAD51D c.413A>G; p.Asn138Ser variant (rs201676898) is reported in the literature in individuals with hereditary cancer syndromes (Boni 2022, Sanchez-Bermudez 2018, Shindo 2017, Tsaousis 2019), and is reported in ClinVar (Variation ID: 127889). This variant is observed in the general population with an overall allele frequency of 0.01% (32/282836 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.061). Based on available information, the clinical significance of this variant is uncertain at this time. References: Boni J et al. A decade of RAD51C and RAD51D germline variants in cancer. Hum Mutat. 2022 Mar;43(3):285-298. PMID: 34923718. Sanchez-Bermudez AI et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018 Jun;61(6):355-361. PMID: 29409816. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 23, 2014	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2024	Observed in individuals with a personal or family history including breast, ovarian, prostate, and other cancers, but also seen in unaffected controls (PMID: 25111073, 25186627, 27443514, 28767289, 29409816, 31159747, 34923718, 33471991, 35893033); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186627, 28767289, 25111073, 27443514, 29409816, 31159747, 34923718, 35893033, 33471991, 21111057, 14704354, 19327148) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 23, 2022	The frequency of this variant in the general population, 0.00054 (19/35438 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (HBOC) (PMIDs: 31159747 (2019), 29409816 (2018), 25186627 (2015)), prostate cancer (PMIDs: 28767289 (2017), 25111073 (2014)), and endometrial cancer (PMID: 27443514 (2016)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2024	Variant summary: RAD51D c.413A>G (p.Asn138Ser) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251474 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013). c.413A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, prostate cancer, endometrial carcinoma, or pancreatic cancer (e.g. Johnson_2014, Tung_2015, Ring_2016, Shindo_2017, Sanchez-Bermudez_2018, Tsaousis_2019). 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: 25111073, 27443514, 29409816, 28767289, 31159747, 25186627). ClinVar contains an entry for this variant (Variation ID: 127889). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.0

DANN

Benign

0.60

DEOGEN2

Benign

0.11

.;T;T;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.75

T;.;T;T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.034

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;N;N;N;N

PROVEAN

Benign

-0.81

.;N;.;.;.;.

REVEL

Benign

0.061

Sift

Benign

0.86

.;T;.;.;.;.

Sift4G

Benign

0.57

T;T;T;T;T;.

Polyphen

0.0

.;B;B;.;.;.

Vest4

0.14, 0.14

MVP

0.40

MPC

0.070

ClinPred

0.012

GERP RS

-2.3

Varity_R

0.025

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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