2-47429809-C-T

Position:

chr2-47429809-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBP6

The NM_001406658.1(MSH2):c.-213C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000143 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MSH2
NM_001406658.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 5.41

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 links:

MSH2 (HGNC:):

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

BP6

Variant 2-47429809-C-T is Benign according to our data. Variant chr2-47429809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232371.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1144C>T	p.Arg382Cys	missense_variant	7/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1144C>T	p.Arg382Cys	missense_variant	7/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251454

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with a personal and family history of colon cancer and polyps, in an individual with family history of breast/ovarian cancer, and in an individual with gastric cancer (Weren et al., 2015; Huang et al., 2018; Lerner-Ellis et al., 2021); Published functional studies suggest this variant has no damaging effect based on results of an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 36451132, 29625052, 21120944, 18822302, 32885271, 25938944, 33357406) -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 31, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Arg382Cys variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or the Mismatch Repair Genes Variant database. The variant was identified in dbSNP (ID: rs752373431) as "With Uncertain significance allele ", in ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, GeneDx, Invitae, Color Genomics), UMD-LSDB (1x as unclassified variant), and in Insight Hereditary Tumors database (1x). The variant was identified in control databases in 9 of 277218 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), European in 4 of 126704 chromosomes (freq: 0.00003), East Asian in 1 of 18870 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.0001); it was not observed in the Latino, Ashkenazi Jewish, and Finnish populations. The p.Arg382 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. -

Lynch syndrome 1

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 16, 2023	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2016	- -

Lynch syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 01, 2020	The MSH2 c.1144C>T (p.Arg382Cys) missense change has a maximal subpopulation frequency of 0.0065% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47656948-C-T). Seven of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), however these predictions have not been confirmed by functional studies. This variant has been reported in one individual with stomach adenocarcinoma (PMID: 29625052) and one individual with colorectal cancer (PMID: 25938944). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with cysteine at codon 382 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A large scale cell based assay measuring resistance to DNA damage induced by 6-thioguanine reported that this variant was functional. This variant has been reported in individuals affected with colonic adenomas (PMID: 25938944) and stomach adenocarcinoma (PMID: 29625052). This variant has been identified in 9/282852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2024	The p.R382C variant (also known as c.1144C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1144. The arginine at codon 382 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in an individual with multiple colon polyps (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2022	This missense variant replaces arginine with cysteine at codon 382 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colonic adenomas (PMID: 25938944). This variant has been identified in 9/282852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 11, 2023

Variant summary: MSH2 c.1144C>T (p.Arg382Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1144C>T has been reported in the literature in individuals affected with Breast/Ovarian cancer (Dorling_2021, Lerner-Ellis_2021), Colorectal Cancer (Weren_2015) and Stomach Cancer (Huang_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A cell-based assay using MSH2 deficient HAP1 cells suggest that the variant confers resistance to DNA damage induced by 6-thioguanine (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 29625052, 25938944, 33471991, 32885271, 33357406). Eight ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance, and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.1

M;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.7

D;D;.;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;.;D

Polyphen

0.99

D;.;.;D

Vest4

0.86

MVP

0.94

MPC

0.029

ClinPred

0.89

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 13

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