chr2-47403283-C-G

Position:

• chr2-47403283-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000251.3(MSH2):​c.92C>G​(p.Thr31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,448,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.06

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06684098).
• BP6: Variant 2-47403283-C-G is Benign according to our data. Variant chr2-47403283-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237415.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.92C>G	p.Thr31Ser	missense_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.92C>G	p.Thr31Ser	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000967 AC: 14 AN: 1448440 Hom.: 0 Cov.: 31 AF XY: 0.00000695 AC XY: 5 AN XY: 719396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 23, 2022

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2023

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 237415). This missense change has been observed in individual(s) with colon cancer (PMID: 29212164). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 31 of the MSH2 protein (p.Thr31Ser). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

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. -

Endometrial carcinoma Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Thr31Ser variant has not been previously observed by our laboratory nor in the literature. This residue is not conserved in mammals and computational analyses (SIFT, BLOSUM, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant amino acid serine (Ser) is present in other mammals including mouse and rat increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is predicted benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.1	N;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.33	N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.82	T;.;T
Sift4G	Benign	0.84	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.099
MutPred		0.44		Loss of phosphorylation at T31 (P = 0.0375);Loss of phosphorylation at T31 (P = 0.0375);Loss of phosphorylation at T31 (P = 0.0375);
MVP		0.75
MPC		0.0067
ClinPred		0.077	T
GERP RS		2.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.074
gMVP		0.23

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: rs746635262; hg19: chr2-47630422;