2-47403249-G-T

Variant summary

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

The NM_000251.3(MSH2):c.58G>T(p.Val20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V20M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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=0.25234675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.58G>T	p.Val20Leu	missense_variant	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.58G>T	p.Val20Leu	missense_variant	1/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447390 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718874

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2019

The p.V20L variant (also known as c.58G>T), located in coding exon 1 of the MSH2 gene, results from a G to T substitution at nucleotide position 58. The valine at codon 20 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.92	L;.;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.43	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.23	T;.;T
Sift4G	Benign	0.29	T;.;T
Polyphen		0.011	B;.;B
Vest4		0.14
MutPred		0.59		Gain of disorder (P = 0.3178);Gain of disorder (P = 0.3178);Gain of disorder (P = 0.3178);
MVP		0.86
MPC		0.0066
ClinPred		0.58	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1198168331; hg19: chr2-47630388;