19-45352249-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000400.4(ERCC2):c.2150C>G(p.Ala717Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:1O:1

Conservation

PhyloP100: 9.00

Variant links:

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 19-45352249-G-C is Pathogenic according to our data. Variant chr19-45352249-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4 link	c.2150C>G	p.Ala717Gly	missense_variant	Exon 22 of 23	ENST00000391945.10	NP_000391.1	P18074-1
ERCC2	XM_011526611.3 link	c.2072C>G	p.Ala691Gly	missense_variant	Exon 21 of 22		XP_011524913.1
ERCC2	XR_001753633.3 link	n.2183C>G		non_coding_transcript_exon_variant	Exon 22 of 24
ERCC2	XR_007066680.1 link	n.2105C>G		non_coding_transcript_exon_variant	Exon 21 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.2150C>G	p.Ala717Gly	missense_variant	Exon 22 of 23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000314

AC:

AN:

251244

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000465

AC:

679

AN:

1461776

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

328

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000506

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000269

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000424

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group D

Pathogenic:3Uncertain:1

May 13, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ERCC2 is predicted to replace alanine with glycine at codon 717, p.(Ala717Gly). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in a helical region. There is a moderate physicochemical difference between alanine and glycine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.2% (23/10,368 alleles) in the Ashkenazi Jewish population, whereas the highest continental population minor allele frequency is 0.04% (47/128,994 alleles) in the European non-Finnish) population. This is consistent with recessive disease. This variant has been detected (always in cis with c.1381C>G, p.Leu461Val) in at least nine individuals with milder/adult-onset xeroderma pigmentosum-Cockayne syndrome complex, trichothiodystrophy, or xeroderma pigmentosum (XP). Of those individuals, five were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by parental/family testing or other methods (PMID: 9195225, 15982307, 16135823, 23232694, 26884178, 35699229). XP complementation analysis was conducted in the cells of most of these individuals, and the XP-D complementation group was identified, which is highly specific for ERCC2-related XP. Multiple lines of computational evidence predict an impact on splicing (SpliceAI, MaxEntScan, NNSplice), and have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). This splice prediction is confirmed by allele-specific RT-PCR. The assay demonstrated that the variant impacts splicing by activation of a leaky cryptic donor site leading to a 55 bp deletion in exon 22 (r.[2146_2190del,2150c>g] p.[Val716_Arg730del,Ala717Gly]; PMID: 25716912). In vitro nucleotide excision repair (NER) and transcription assays in NER-deficient cell lines showed p.Val716_Arg730del exhibited defective repair and transcriptional activity, while p.Ala717Gly exhibited efficient repair and transcriptional activity. The combined p.[Leu461Val;Ala717Gly] exhibited intermediate activity (PMID: 25716912). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP3, PP4. -

Apr 14, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 717 of the ERCC2 protein (p.Ala717Gly). This variant is present in population databases (rs144564120, gnomAD 0.2%). This missense change has been observed in individuals with breast and ovarian cancer and xeroderma pigmentosum and trichothiodystrophy (PMID: 15982307, 23232694, 25716912, 26884178, 27504877, 29607586). This variant is also known as del 716‚Äì730 or g.18339C>G. ClinVar contains an entry for this variant (Variation ID: 134102). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 7585650, 15982307, 25716912). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERCC2: PS3, PM2, PM3, PP3 -

Apr 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies suggest that the c.2150C>G variant creates a cryptic splice donor site upstream of the natural splice site, leading to an in-frame deletion of 15 amino acids (PMID: 7585650); Published functional studies also suggest that A717G was similar to wildtype in UV survival assays and TFIIH binding, but when expressed in cis with L461V, cells were more sensitive at high doses of UV; however, the significance of this result is unclear due to a lack known controls (PMID: 25716912); In silico analysis supports that this missense variant does not alter protein structure/function, but has a deleterious effect on splicing; Observed almost always on the same allele (in cis) with the L461V variant (PMID: 7585650, 9195225, 23221806, 25716912, 26884178); This variant is associated with the following publications: (PMID: 24728327, 32239545, 23221806, 26884178, 25716912, 9195225, 37762649, 36845387, 35988656, 34426522, 31589614, 34308104, 22234153, 8571952, 16135823, 31980526, 33726816, 23232694, 27504877, 29607586, 30676620, 15982307, 17020410, 7585650) -

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive

Pathogenic:2

Apr 13, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified

Pathogenic:1

Jan 20, 2016

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum

Pathogenic:1

Jan 04, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ERCC2 c.2150C>G (p.Ala717Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. It has always been reported in cis with c.1381C>G (p.Leu461Val). Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in splicing-out of the last 45 bases of exon 22 resulting in r.[1381c>g;2146_2190del], which is translated into p.[L461V;V716_R730del] (Horibata_2015). The variant allele was found at a frequency of 0.00031 in 251244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum/Trichothiodystrophy (0.00031 vs 0.00061), allowing no conclusion about variant significance. c.2150C>G has been reported in the literature always a complex allele in cis with c.1381C>G (p.Leu461Val) in compound heterozygous genotypes with other pathogenic alleles in multiple individuals with features of Xeroderma Pigmentosum and Trichothiodystrophy (example, Takayama_1996, Moslehi_2012, Fujimoto_2005, Zhou_2013, Fassihi_2016, Horibata_2015). This complex allele has also been reported in individuals with various cancers, although these findings have not been ascertained in the context of this evaluation. These data indicate that the variant in its complex allele configuration is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the complex allele on protein function (example, Horibata_2015). The most pronounced variant effect abolishes the helicase, Nucleotide Excision Repair (NER) activity and the transcriptional activity of TFIIH. However, although individually, p.Leu461Val and p.Ala717Gly possessed full NER activity (comparable to p.WT), the combined mutant p.[Leu461Val; Ala717Gly] possessed only partial NER activity. Due to the data presented as immunoprecipitation data on blots, an exact residual activity for the combined mutant cannot be ascertained from this report. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, as a surrogate representation of its complex allele configuration, this variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 15, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2150C>G (p.A717G) alteration is located in coding exon 22 of the ERCC2 gene. This alteration results from a C to G substitution at nucleotide position 2150, causing the alanine (A) at amino acid position 717 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.03% (87/282626) total alleles studied. The highest observed frequency was 0.22% (23/10368) of Ashkenazi Jewish alleles. This mutation has been reported in conjunction with additional ERCC2 alterations in individuals with xeroderma pigmentosum and trichothiodystrophy (Takayama, 1995; Takayama, 1997; Fujimoto, 2005; Orioli, 2013; Zhou, 2013; Fassihi, 2016). Fibroblast cell lines derived from individuals with this mutation demonstrated aberrant splicing, expected to result in an in-frame deletion of 15 amino acids (V716_R730del) (Takayama, 1995; Horibata, 2015). Additional functional assays showed that XPD protein with the V716_R730 deletion is defective in nucleotide excision repair activity and could not form the TFIIH complex (Horibata, 2015). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

ERCC2-related disorder

Pathogenic:1

Jan 09, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ERCC2 c.2150C>G (p.Ala717Gly) variant creates a new splice donor site which results in altered splicing leading to a 15 amino acid deletion (p.Val716_Arg730del) (Takayama et al. 1995; Horibata et al. 2015). The p.Val716_Arg730del variant is described in at least six studies, in which it is always found in cis with a missense variant, c.1381C>G (p.Leu461Val), to give the complex allele: [c.1381C>G (p.Leu461Val); c.2150C>G (p.Val716_Arg730del)] (Takayama et al. 1995; Takayama et al. 1997; Moslehi et al. 2012; Orioli et al. 2013; Zhou et al. 2013; Horibata et al. 2015). The complex allele (p.Leu461Val; p.Val716_Arg730del) has been reported in a compound heterozygous state with another missense variant in a total of 16 individuals with either xeroderma pigmentosum (XP) or trichothiodystrophy. Orioli et al. (2013) report the (p.Leu461Val; p.Val716_Arg730del) allele in a compound heterozygous state with a missense variant in a patient with a severe XP phenotype. The patient had 48% of normal transcription factor TFIIH levels in fibroblasts and 10% of typical UV-induced DNA repair synthesis ability. Horibata et al. (2015) performed functional studies demonstrating that the (p.Leu461Val; p.Val716_Arg730del) allele was functionally null in nucleotide excision repair and not able to form the TFIIH complex. The p.Ala717Gly and p.Leu461Val variants in isolation performed similarly to wild type in nucleotide excision repair and were able to fully or partly form the TFIIH complex and rescue the UV hypersensitivity. Zhou et al. (2013) also showed that the (p.Leu461Val; p.Val716_Arg730del) allele exhibited decreased DNA repair. The p.Ala717Gly variant is reported at a frequency of 0.0005124 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the (p.Leu461Val; p.Val716_Arg730del) allele is classified as pathogenic for ERCC2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Trichothiodystrophy 1, photosensitive

Pathogenic:1

Apr 27, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

N;N;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0070

D;D;.

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.015

B;B;.

Vest4

0.62

MVP

0.89

MPC

0.30

ClinPred

0.64

GERP RS

5.3

Varity_R

0.42

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.87

Position offset: 5

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