rs63751455

chr2-47412496-G-Achr2-47412496-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000251.3(MSH2):c.728G>A(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,374 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. R243W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 9.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• BP6: Variant 2-47412496-G-A is Benign according to our data. Variant chr2-47412496-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91189.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.728G>A	p.Arg243Gln	missense_variant	4/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.728G>A	p.Arg243Gln	missense_variant	4/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251398 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1459344 Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15 AN XY: 726218

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history including colorectal and other cancers (Auclair 2006, Moussa 2011, Ziada-Bouchaar 2016, Mandelker 2017); Published functional studies demonstrate lack of cell survival following MNNG-induced DNA damage, suggesting neutrality (Bouvet 2019); This variant is associated with the following publications: (PMID: 16395668, 21311894, 18383312, 26247049, 27468915, 26333163, 28873162, 26116798, 24953332, 31248416, 30998989) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2022	Variant summary: MSH2 c.728G>A (p.Arg243Gln) 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 1.6e-05 in 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728G>A has been reported in the literature in individuals affected with hereditary nonpolyposis colorectal cancer and colorectal cancer (Auclair_2006, Zaida-Bouchaar_2017, Castillejo_2014, Moussa_2011, Bodo_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants were reported in 4 patients described in the literature, including the co-occurrence of homozygous PMS2 large deletions in a patient with CMMR (MSH2 c.1413dupA, p.Pro472ThrfsX4; MSH2 c.1030C>T, p.Gln344X ; PMS2 c.2275+210_2446-1356del, p.Ala759Glyfs*8), providing supporting evidence for a benign role. Two publications report splicing evidence showing no impact on splicing by the variant (Van der Klift_2015, Auclair_2006). Additionally, another functional study based on the proportion of cells that undergo death following exposure to methylating agents reported the variant to be neutral (Bouvet_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant. -

Lynch syndrome 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 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: 25085752]. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2023	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The MSH2 p.Arg243Gln variant was identified in 3 of 224 proband chromosomes (frequency: 0.01) from Algerian, French and Tunisian individuals or families with Lynch syndrome or CRC (Ziada-Bouchaar 2017, Moussa 2011, Auclair 2006). In these studies, 2 of the probands had co-occurring pathogenic MSH2 variants (c.1030C>T/ p.Gln344X and c.1413dupA/p.Pro472ThrfsX4). The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.7234_7235insG, p.Thr2412Serfs*2) increasing the likelihood the MSH2 c.728G>A variant may not have clinical significance. In functional studies using patient RNA analysis and minigene splicing, both assays showed normal splicing (van der Klift 2015, Auclair 2006). A bioinformatics tool, multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), classified the variant as neutral (Chao 2008). The variant was also identified in dbSNP (ID: rs63751455) “With Uncertain significance allele”, ClinVar (classified uncertain significance, reviewed by an expert panel (2013); submitters: INSIGHT, Invitae, Ambry Genetics, GeneDx and 3 other laboratories), and UMD-LSDB (4x classified as UV). The variant was identified in control databases in 3 of 246198 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 2 of 33578 chromosomes (freq: 0.00006) and European Non-Finnish in 1 of 111672 chromosomes (freq: 0.000009); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The p.Arg243 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gln variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.016	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.82
MutPred		0.40		Loss of MoRF binding (P = 0.0218);.;Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);
MVP		0.95
MPC		0.033
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.85
gMVP		0.58

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

Other links and lift over

dbSNP: rs63751455; hg19: chr2-47639635;