2-47403205-C-A

Variant names:

• chr2-47403205-C-A
• rs56170584
• NM_000251.3:c.14C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:5
• Conservation: PhyloP100: 6.99
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-47403205-C-A is Benign according to our data. Variant chr2-47403205-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 90682.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000318 AC: 7 AN: 220468 AF XY: 0.0000250

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 41 AN: 1445928 Hom.: 0 Cov.: 31 AF XY: 0.0000306 AC XY: 22 AN XY: 717926

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 42180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.000997 AC: 39 AN: 39136

South Asian (SAS) AF: 0.00 AC: 0 AN: 83698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105696

Other (OTH) AF: 0.0000334 AC: 2 AN: 59808

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000002), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000292 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000249 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Uncertain:3 Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 22, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 27363726]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Sep 26, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Oct 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 22, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome Uncertain:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Uncertain significance allele”, 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. -

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 28, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 29, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Uncertain significance allele”, 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

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary nonpolyposis colon cancer Benign:1

Jan 27, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.2	L;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.70	T
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	D
GERP RS		5.5
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.48
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs56170584; hg19: chr2-47630344;