2-47416398-C-G

Position:

chr2-47416398-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM5PP3_StrongBP6

The NM_000251.3(MSH2):c.1045C>G(p.Pro349Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,108 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P349L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7

Conservation

PhyloP100: 7.76

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 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47416399-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

BP6

Variant 2-47416398-C-G is Benign according to our data. Variant chr2-47416398-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90512.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=7, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1045C>G	p.Pro349Ala	missense_variant	6/16	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.1045C>G	p.Pro349Ala	missense_variant	6/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.000288

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:

0.000957

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251434

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000459

AC:

AN:

1460988

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 11, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 09, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2020	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. -

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: MSH2 c.1045C>G (p.Pro349Ala) results in a non-conservative amino acid change located in the 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 9.1e-05 in 251434 control chromosomes, predominantly at a frequency of 0.00035 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (9.1e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.1045C>G, has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome (Hansen_2017, Akcay_2020, Ferrer-Avargues_2021) and with other tumor phenotypes, which were mostly outside of the Lynch syndrome tumor spectrum (e.g. Rubio-Del-Campo_2008, Cragun_2014, Landa_2016, Jalkh_2017, Zidan_2017, Dorling_2021), but the variant was also found in healthy controls (e.g. Dorling_2021). In addition, in one of the reported CRC cases a co-occurrence with other pathogenic variant has been reported (MSH2 c.223_224del (p.Leu75AlafsTer), Ferrer-Avargues_2021), providing supporting evidence for a benign role. Multiple publications reported experimental evidence evaluating an impact on protein function, and all of them showed no damaging effect for this variant (Houlleberghs_2016, Bouvet_2019, Jia_2021). Of note, several other missense variants affecting the same residue (e.g. P349L and P349R) were found to be deleterious in these assays (Houlleberghs_2016, Jia_2021), suggesting that although P349 may be critical for protein function, the effect of missense variants at this residue strongly depends on the specific amino acid substitution. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 25637381, 30998989, 24506336, 33471991, 33630411, 28195393, 26951660, 28202063, 33357406, 24763289, 26878173, 31391288, 28640387, 18325052, 31297992, 28828701, 35264596, 35245693, 36845387). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 13, 2020	The p.Pro349Ala variant in MSH2 is classified as likely benign because it has been identified in 0.08% (8/10366) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Lynch syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2023	The MSH2 c.1045C>G (p.Pro349Ala) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 28195393 (2017), 28640387 (2017), 32658311 (2021), 33630411 (2021)), breast cancer (PMIDs: 28202063 (2017), 30306255 (2018), 34371384 (2021), 35245693 (2022), 35264596 (2022), 35534704 (2022)), and cervical cancer (PMID: 24506336 (2014)). This variant was also reported to occur with a pathogenic variant in the same MSH2 gene (PMID: 33630411 (2021)) or the BRCA1 gene (PMID: 28202063 (2017)), suggesting this variant may not be the primary cause of disease. Functional studies predicted the variant to be neutral using indirect cell survival assays of MMR function (PMIDs: 26951660 (2016), 30998989 (2019), 33357406 (2021)), however, different amino acid changes at the same codon, p.Pro349Leu and p.Pro349Arg, showed defective MMR function and further research is needed. The frequency of this variant in the general population, 0.00077 (8/10366 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30998989, 29887214, 18325052, 31297992, 30306255, 28873162, 17720936, 17531815, 21239990, 18951462, 15342696, 28640387, 28828701, 26951660, 28301460, 28584132, 26878173, 27720647, 28195393, 28202063, 24506336, 22949387, 26333163, 25203624, 25637381, 24763289) -

Hereditary nonpolyposis colon cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Jan 05, 2021

ClinVar contains an entry for this variant (ID:90512) which has conflicting classifications. Based on data in gnomAD, the frequency in the Latino population and Ashkenazi Jewish population is higher than expected for a pathogenic MSH2 variant. In a Lebanese family, the variant has been observed to co-occur with a pathogenic variant that could explain the patient disease phenotype (PMID 28202063). -

Papillary renal cell carcinoma type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Sep 10, 2024

According to the ClinGen InSiGHT ACMG MSH2 v1.0.0 criteria we chose these criteria: PP3 (medium pathogenic): prior Propability: 0,87: mod, BS1 (strong benign): GnomAD v4 Grpmax filtering allele frequency = 0.0002341 (thus, ≥ 0.0001 and < 0.001 (0.01-0.1%)), BS3 (strong benign): PMID: 33357406 / Jia et. al (2021): LOF Score of -2.77 in functional assay. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

H;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.9

D;D;.;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.95

MVP

0.98

MPC

0.036

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.70

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