2-47408463-C-G

Position:

chr2-47408463-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001406656.1(MSH2):c.-722C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,611,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MSH2
NM_001406656.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 2.23

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 2-47408463-C-G is Benign according to our data. Variant chr2-47408463-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91041.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7, Benign=2}. Variant chr2-47408463-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.274C>G	p.Leu92Val	missense_variant	2/16	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.274C>G	p.Leu92Val	missense_variant	2/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151434

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251214

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1459792

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73930

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 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	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 08, 2023	A heterozygous missense variation in exon 2 of the MSH2 gene that results in the amino acid substitution of Valine for Leucine at codon 92 was detected. The observed variant c.274C>G (p.Leu92Val) has not been reported in the 1000 genomes and has a minor allele frequency of 0.005% in the gnomAD database. The observed variation has previously been reported in an individual with family history of Lynch syndrome (Betz B et al. 2010) and it lies in the MutS domain I of the MSH2_HUMAN protein. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2 tools. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This missense variant replaces leucine with valine at codon 92 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. The primary cause of the disease is not clear. This variant has been identified in 15/251214 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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 12, 2022	This alteration is classified as 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. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Leu92Val variant has been reported in the literature from an individual in the German HNPCC consortium in a study that examined several in-silico programs (Betz 2010); "no changes" were predicted for this variant. The variant was also identified in the InSight, Medical center Groningen and Memorial University MMR databases. This residue is conserved in mammals but not in lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant is identified by our laboratory in one individual with a co-occuring pathogenic variant, increasing the likelihood this variant does not have clinical significance. In summary, the clinical significance of this variant cannot be determined with certainty, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	This variant is associated with the following publications: (PMID: 19669161, 26333163, 28135145) -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 14, 2024

This missense variant replaces leucine with valine at codon 92 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161), and an individual affected with a pediatric central nervous system tumor (PMID: 38139220). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. This variant has been identified in 15/251214 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. -

Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 28, 2019

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5. This variant was detected in homozygous state. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 22, 2023

Variant summary: MSH2 c.274C>G (p.Leu92Val) results in a conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251214 control chromosomes, predominantly at a frequency of 0.00026 within the South Asian subpopulation in the gnomAD database. This subpopulation frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), allowing no clear conclusion about variant significance. The variant, c.274C>G, has been reported in the literature in heterozygous state in individuals affected with Lynch Syndrome related tumors (Betz_2010, Yurgelun_2017), and unspecified tumor phenotype (Bhai_2021). However, co-occurrences with other pathogenic variants have been reported (MSH6 c.2653A>T, p.Lys885X in the UMD database; and MSH2 exons 1-6 deletion in Yurgelun_2017), providing supporting evidence for a benign role. In addition, the variant was also reported in homozygous state in a patient with constitutional mismatch repair deficiency syndrome (Taeubner_2018, Brozou_2018, Gallon_2019), however the patient also carried a homozygous MSH6 variant, and functional studies performed on patient derived samples suggested that the MSH2 variant was unlikely to be disease causing in this patient (Taeubner_2018, Gallon_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19669161, 29302048, 28929227, 30740824, 34326862, 28135145). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments, i.e. likely pathogenic (n=1), VUS (n=6), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Benign

0.74

DEOGEN2

Uncertain

0.69

D;D;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.3

M;.;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.8

N;D;N;.;N

REVEL

Pathogenic

0.75

Sift

Benign

0.30

T;D;T;.;T

Sift4G

Benign

0.39

T;D;T;.;T

Polyphen

0.99

D;.;.;.;D

Vest4

0.89

MutPred

0.74

Gain of MoRF binding (P = 0.082);.;.;Gain of MoRF binding (P = 0.082);Gain of MoRF binding (P = 0.082);

MVP

0.95

MPC

0.024

ClinPred

0.35

GERP RS

5.3

Varity_R

0.71

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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