rs56170584

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000251.3(MSH2):c.14C>A(p.Pro5Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000282 in 1,598,272 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:5

Conservation

PhyloP100: 6.99

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.14C>A	p.Pro5Gln	missense_variant	1/16	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.14C>A	p.Pro5Gln	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

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:

0.000770

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:

220468

Hom.:

AF XY:

0.0000250

AC XY:

AN XY:

120124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000418

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000284

AC:

AN:

1445928

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

717926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000997

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000249

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 14, 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: 27363726]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2023	This missense variant replaces proline with glutamine at codon 5 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). An RNA study reported no splicing defect detected in carrier RNA (PMID: 16425354; InSiGHT database). However, a functional study reported that this variant showed RNA expression defect in transfected cell lines (PMID: 28494185). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with colorectal, endometrial and gastric cancer (PMID: 14514376, 23760103, 26845104, 29050249, 31054147, 31307542, 33294277, 33309985), breast and ovarian cancer (PMID: 28580595, 30982232, 32019277, 32068069), pancreatic cancer (PMID: 32980694), and cancer unaffected controls (PMID: 32980694, 33309985). This variant has been identified in 8/251846 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2021	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	curation	Sema4, Sema4	Aug 25, 2021	- -

Lynch syndrome

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Pro5Gln variant was identified in 2 of 3138 proband chromosomes (freq: 0.001) from individuals with gastric cancer and was present in 3 of 4098 control chromosomes (freq: 0.001) from healthy Japanese individuals (Shirts 2016, Kim 2017, Yamaguchi-Kabata 2018). The variant was also identified in the following databases: dbSNP (rs56170584) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Counsyl and three other submitters). The variant was not identified in the UMD LSDB database. The variant was identified in control databases in 7 of 214510 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 7 of 15668 chromosomes (freq: 0.0004) while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish or South Asian populations. The p.Pro5Gln residue is conserved in mammals but not in more distantly related organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant was identidied in one individual with gastric cancer and first-degree relatives with melanoma and breast cancer, although the proband demonstrated normal IHC and MMR levels (Kim 2017). One study showed greatly reduced mRNA and protein levels for this variant, possibly due to a predicted circular loop RNA structure (Arora 2017). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces proline with glutamine at codon 5 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). An RNA study reported no splicing defect detected in carrier RNA (PMID: 16425354; InSiGHT database). However, a functional study reported that this variant showed RNA expression defect in transfected cell lines (PMID: 28494185). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with colorectal, endometrial and gastric cancer (PMID: 14514376, 23760103, 26845104, 29050249, 31054147, 31307542, 33294277, 33309985), breast and ovarian cancer (PMID: 28580595, 30982232, 32019277, 32068069), pancreatic cancer (PMID: 32980694), and cancer unaffected controls (PMID: 32980694, 33309985). This variant has been identified in 8/251846 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with MSH2-related cancers; tumor IHC analyses did not consistently show loss of MSH2 protein (Sun et al., 2004; Chao et al., 2019; Tian et al., 2019); Published functional studies are conflicting: showed defective RNA and protein expression as well as cell viability and response to DNA-damaging agents in one study (Arora et al., 2017) and normal mismatch repair function and cell growth rates in another (Jia et al., 2020); This variant is associated with the following publications: (PMID: 14514376, 29192238, 15046089, 16425354, 18383312, 26333163, 26845104, 28580595, 29050249, 28706299, 31386297, 32255556, 32566746, 30798936, 35538921, 31569399, 18822302, 21120944, 30982232, 33357406, 33471991, 33309985, 32019277, 23760103, 31307542, 35057767, 33294277, 30374176, 31054147, 28494185) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 29, 2023

Variant summary: MSH2 c.14C>A (p.Pro5Gln) results in a non-conservative amino acid change in 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 220468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.14C>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with a variety of cancers such as stomach/gastric, breast, Lynch tumors (example, Wang_2005, Shirts_2015, Kim_2017, Xie_2018, Chao_2019, Kiyozumi_2019, Tian_2019, Tsai_2019, Wang_2019, Kim_2022). Some of these reports included individuals with conflicting immunohistochemistry (IHC) findings such as normal IHC (example, Shirts_2015), stable MSI and normal IHC (example, Chao_2019) and at-least one report of an individual with colorectal cancer and negative staining for MSH2 but positive staining for MLH1, MSH6 and PMS2 (example, Tian_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.3261dupC, p.Phe1088fs, Kim_2022), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that cells expressing the variant had nondetectable levels of MSH2 RNA and protein expression and impaired DNA-damage response in-vitro (Arora_2017). The following publications have been ascertained in the context of this evaluation (PMID: 26845104, 16425354, 28494185, 29050249, 28580595, 30374176, 30982232, 31307542, 31386297, 31054147, 35884469). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Pro5Gln variant was identified in 2 of 3138 proband chromosomes (freq: 0.001) from individuals with gastric cancer and was present in 3 of 4098 control chromosomes (freq: 0.001) from healthy Japanese individuals (Shirts 2016, Kim 2017, Yamaguchi-Kabata 2018). The variant was also identified in the following databases: dbSNP (rs56170584) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Counsyl and three other submitters). The variant was not identified in the UMD LSDB database. The variant was identified in control databases in 7 of 214510 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 7 of 15668 chromosomes (freq: 0.0004) while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish or South Asian populations. The p.Pro5Gln residue is conserved in mammals but not in more distantly related organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant was identidied in one individual with gastric cancer and first-degree relatives with melanoma and breast cancer, although the proband demonstrated normal IHC and MMR levels (Kim 2017). One study showed greatly reduced mRNA and protein levels for this variant, possibly due to a predicted circular loop RNA structure (Arora 2017). 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Hereditary nonpolyposis colon cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Jan 27, 2023

Internal laboratory data reveals that this variant has been detected in several individuals whose personal histories, family histories, or tumor profiles were not consistent with Lynch syndrome (internal data, unpublished). -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

D;.;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0070

D;.;T

Polyphen

0.91

P;.;D

Vest4

0.80

MutPred

0.68

Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);

MVP

0.96

MPC

0.032

ClinPred

0.77

GERP RS

5.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.74

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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