rs63751099

Positions:

• chr2-47403219-C-A
• chr2-47403219-C-G
• chr2-47403219-C-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.28C>A​(p.Gln10Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.96

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20983204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.28C>A	p.Gln10Lys	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.28C>A	p.Gln10Lys	missense_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719316

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 13, 2012

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2021

The p.Q10K variant (also known as c.28C>A), located in coding exon 1 of the MSH2 gene, results from a C to A substitution at nucleotide position 28. The glutamine at codon 10 is replaced by lysine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 186 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This alteration has also been identified in a cohort of 572 atherosclerosis patients with no clinical history of cancer (Pinard A et al. Hum Mutat, 2016 12;37:1299-1307). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.035	N;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.37	N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.36	T;.;T
Sift4G	Benign	0.78	T;.;T
Polyphen		0.017	B;.;B
Vest4		0.38
MutPred		0.35		Gain of ubiquitination at Q10 (P = 0.0203);Gain of ubiquitination at Q10 (P = 0.0203);Gain of ubiquitination at Q10 (P = 0.0203);
MVP		0.97
MPC		0.0061
ClinPred		0.28	T
GERP RS		3.6
Varity_R		0.35
gMVP		0.41

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: rs63751099; hg19: chr2-47630358;