2-47410284-A-G

Position:

chr2-47410284-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBP6

The NM_000251.3(MSH2):c.557A>G(p.Asn186Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,936 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 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:5

Conservation

PhyloP100: 9.25

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 3 ACMG points.

PM1

In a helix (size 9) in uniprot entity MSH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000251.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

BP6

Variant 2-47410284-A-G is Benign according to our data. Variant chr2-47410284-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91133.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=9, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.557A>G	p.Asn186Ser	missense_variant	3/16	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.557A>G	p.Asn186Ser	missense_variant	3/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251480

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000834

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2024	Observed in individuals with suspected Lynch syndrome and/or breast cancer, but also in unaffected controls (PMID: 11606497, 26580448, 27601186, 28874130, 32980694, 33471991, 35449176); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11606497, 12419761, 27273229, 26333163, 27601186, 27720647, 26580448, 28874130, 29752822, 31159747, 31391288, 17531815, 32980694, 33471991, 35449176, 18822302, 21120944, 36243179, 27978560, 36845387) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2024	The MSH2 c.557A>G (p.Asn186Ser) variant has been reported in the published literature in individuals with Lynch syndrome or Lynch syndrome-related cancer (PMID: 31391288 (2020), 28874130 (2017), 27273229 (2017), 27978560 (2016), 27601186 (2016)), breast and/or ovarian cancer (PMID: 31159747 (2019), 29752822 (2018)), and rhabdosarcoma (PMID: 26580448 (2015)). This variant has also been identified in reportedly healthy individuals (PMID: 32980694 (2020), 11606497 (2001)). In an individual with colon cancer, this variant co-occurred with a deleterious frameshift variant in the MSH2 gene, suggesting the c.557A>G (p.Asn186Ser) variant may not be the cause of disease (PMID: 27978560 (2016)). The frequency of this variant in the general population, 0.0002 (7/35440 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2022	The MSH2 c.557A>G; p.Asn186Ser variant (rs151129360) is reported in the literature in individuals with suspected Lynch syndrome, colorectal cancer, breast cancer, or hereditary cancer predisposition syndrome (Buchanan 2017, Li 2019, Rossi 2017, Tsaousis 2019). Immunohistochemistry (IHC) staining of tumor sample containing this variant was normal, but showed high microsatellite instability (MSI-H) (Buchanan 2017). This variant is also reported in ClinVar (Variation ID: 91133). It is found in the general population with an overall allele frequency of 0.0095% (27/282864 alleles) in the Genome Aggregation Database. The asparagine at codon 186 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.769). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Buchanan DD et al. Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. J Gastroenterol Hepatol. 2017 Feb;32(2):427-438. PMID: 27273229. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. PMID: 29752822. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. PMID: 28874130. 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:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 05, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2023	Variant summary: MSH2 c.557A>G (p.Asn186Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251626 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (9.5e-05 vs 0.00057), allowing no conclusion about variant significance. c.557A>G has been reported in the literature in individuals affected with Lynch Syndrome (examples: Lagerstedt-Robinson_2016, Buchanan_2016, Perlman_2016, Mu_2016, Rossi_2017) or breast cancer (examples: Li_2018, Hu_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one pathogenic co-occurring evariant has been reported (Pearlman_2016, MSH2 c.2096C>A, p.Ser699X), providing supporting evidence for a benign role. A recent study analyzed MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios to compute a tumour characteristic likelihood ratio (TCLR), that was further assessed in combination with in-silico predictors, and a multifactorial variant prediction (Li_2010). This specific variant was predicted to be likely benign based on this model (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=8) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

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

Mar 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.3

M;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

D;D;D;.;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D;D;.;D

Sift4G

Uncertain

0.048

D;D;D;.;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.81

MVP

0.96

MPC

0.038

ClinPred

0.88

GERP RS

4.6

Varity_R

0.81

gMVP

0.69

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