rs1386630417

Positions:

• chr2-47429912-A-C
• chr2-47429912-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000251.3(MSH2):​c.1247A>C​(p.Asn416Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.579

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21445283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1247A>C	p.Asn416Thr	missense_variant	7/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1247A>C	p.Asn416Thr	missense_variant	7/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2020

This variant has not been reported in the literature in individuals with MSH2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 416 of the MSH2 protein (p.Asn416Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.40	N;.;.;.
MutationTaster	Benign	0.78	D;D;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.23	T;T;.;T
Sift4G	Benign	0.50	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.50
MutPred		0.55		Gain of disorder (P = 0.2626);.;Gain of disorder (P = 0.2626);Gain of disorder (P = 0.2626);
MVP		0.98
MPC		0.0065
ClinPred		0.11	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47657051;