2-47480788-C-A

Position:

• chr2-47480788-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000251.3(MSH2):​c.2551C>A​(p.Leu851Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,824 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 1.90

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2551C>A	p.Leu851Ile	missense_variant	15/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2551C>A	p.Leu851Ile	missense_variant	15/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251450 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

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: 0.00000274 AC: 4 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2022	Variant summary: MSH2 c.2551C>A (p.Leu851Ile) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) 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 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2551C>A has been reported in the literature in at-least one individual affected with Lynch Syndrome associated cancer (Yap_2009). The variant has also been observed in one individual affected with breast cancer and two unaffaected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Lynch syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 18, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2023	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	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces leucine with isoleucine at codon 851 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with Lynch syndrome (PMID: 18726168). In a large breast cancer case-control study, this variant was reported in one affected individual and two unaffected control individuals (PMID: 33471991). This variant has been identified in 4/251450 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. -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

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

Jan 01, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2017

This variant is denoted MSH2 c.2551C>A at the cDNA level, p.Leu851Ile (L851I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). This variant was observed within a Sinhalese family with Lynch syndrome-associated cancer (Yap 2009). MSH2 Leu851Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu851Ile is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain" due to insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MSH2 Leu851Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance." -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.6	M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.68
MutPred		0.79		Loss of catalytic residue at L851 (P = 0.0747);.;Loss of catalytic residue at L851 (P = 0.0747);Loss of catalytic residue at L851 (P = 0.0747);
MVP		0.83
MPC		0.025
ClinPred		0.76	D
GERP RS		4.0
Varity_R		0.84
gMVP		0.42

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: rs267608015; hg19: chr2-47707927;