rs587778271

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000400.4(ERCC2):c.1703_1704del(p.Phe568TyrfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F568F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 8.55

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-45353295-TAA-T is Pathogenic according to our data. Variant chr19-45353295-TAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC2	NM_000400.4 linkuse as main transcript	c.1703_1704del	p.Phe568TyrfsTer2	frameshift_variant	18/23	ENST00000391945.10
ERCC2	XM_011526611.3 linkuse as main transcript	c.1625_1626del	p.Phe542TyrfsTer2	frameshift_variant	17/22
ERCC2	XR_001753633.3 linkuse as main transcript	n.1736_1737del		non_coding_transcript_exon_variant	18/24
ERCC2	XR_007066680.1 linkuse as main transcript	n.1658_1659del		non_coding_transcript_exon_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.1703_1704del	p.Phe568TyrfsTer2	frameshift_variant	18/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251240

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461844

Hom.:

AF XY:

0.0000963

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000191

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000378

Hom.:

Bravo

AF:

0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2022	Identified with a second ERCC2 variant in individuals with features of xeroderma pigmentosum and trichothiodystrophy in the published literature (Broughton et al., 2001; Zhou et al., 2010), and in a patient with trichothiodystrophy referred for genetic testing at GeneDx; Reported previously in the heterozygous state in association with breast and/or ovarian cancer susceptibility (Lhota et al., 2016; Maxwell et al., 2016; Yehia et al., 2018; Rump et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26822949, 27153395, 27504877, 29684080, 11709541, 24728327, 20633800, 26689913, 31589614, 29625052) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Phe568Tyrfs*2) in the ERCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC2 are known to be pathogenic (PMID: 9238033, 11335038, 19085937, 19934020). This variant is present in population databases (rs587778271, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of xeroderma pigmentosum with trichothiodystrophy (PMID: 11709541). ClinVar contains an entry for this variant (Variation ID: 134095). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ERCC2: PVS1, PS3:Supporting -

Xeroderma pigmentosum, group D

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 2018	The ERCC2 c.1703_1704delTT (p.Phe568TyrfsTer2) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Phe568TyrfsTer2 variant has been reported in at least two studies, in which it is found in a compound heterozygous state in two unrelated individuals with features of both xeroderma pigmentosa (XP) and trichothiodystrophy (TTD) (Broughton et al., 2001; Zhou et al., 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000174 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants and the limited number of cases, this variant is classified as likely pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Xeroderma pigmentosum

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 12, 2023

Variant summary: ERCC2 c.1703_1704delTT (p.Phe568TyrfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1984C>T [p.Gln662Ter], c.2005del [p.Arg669fs]). The variant allele was found at a frequency of 0.0001 in 282568 control chromosomes (gnomAD), predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (0.0001 vs 0.00061), allowing no conclusion about variant significance. c.1703_1704delTT has been reported in the literature in compound heterozygous individuals affected with Xeroderma Pigmentosum (Broughton_2001) and Trichothiodystrophy (Zhou_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and six as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.1703_1704delTT (p.F568Yfs*2) alteration, located in exon 18 (coding exon 18) of the ERCC2 gene, consists of a deletion of 2 nucleotides from position 1703 to 1704, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.01% (29/282568) total alleles studied. The highest observed frequency was 0.019% (25/128994) of European (non-Finnish) alleles. This variant has been reported in combination with a second ERCC2 variant of unknown significance in an individual with clinical features consistent with ERCC2-related spectrum disorders (Zhou, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

Cerebrooculofacioskeletal syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

ERCC2-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2023

The ERCC2 c.1703_1704delTT variant is predicted to result in a frameshift and premature protein termination (p.Phe568Tyrfs*2). This variant has been reported in the compound heterozygous state in two individuals with xeroderma pigmentosum (Broughton et al 2001. PubMed ID: 11709541, reported as 1781-1782 del TT; Zhou et al. 2010. PubMed ID: 20633800). This variant has also been reported in the heterozygous state in individuals with cancer, but it was also reported in controls (see for example, Lhota F et al 2016. PubMed ID: 26822949; Maxwell KN et al 2016. PubMed ID: 27153395). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-45856553-TAA-T). Functional studies in vitro indicated that this variant disrupts excision repair (Rump A et al 2016. PubMed ID: 27504877), and frameshift variants in ERCC2 are expected to be pathogenic. Taken together, this variant is of uncertain clinical significance for predisposition to cancer; it is interpreted as pathogenic for autosomal recessive xeroderma pigmentosum. -

Leukodystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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