rs1114167845

chr2-47414416-C-Achr2-47414416-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_000251.3(MSH2):c.940C>A(p.Gln314Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q314H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 0.8088
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59

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 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47414418-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 483693.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.940C>A	p.Gln314Lys	missense_variant, splice_region_variant	5/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.940C>A	p.Gln314Lys	missense_variant, splice_region_variant	5/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 45208 Hom.: 0 Cov.: 14 FAILED QC

Gnomad AFR AF: 0.0000914

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000373

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000210 AC: 92 AN: 438710 Hom.: 0 Cov.: 22 AF XY: 0.000191 AC XY: 44 AN XY: 230554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000217

Gnomad4 SAS exome AF: 0.0000706

Gnomad4 FIN exome AF: 0.0000398

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000334

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000442 AC: 2 AN: 45234 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 19878

Gnomad4 AFR AF: 0.0000913

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000373

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.98	N;N;.;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	D;D;.;D
Sift4G	Uncertain	0.034	D;D;.;D
Polyphen		0.27	B;.;.;P
Vest4		0.80
MutPred		0.58		Gain of ubiquitination at Q314 (P = 0.0238);.;Gain of ubiquitination at Q314 (P = 0.0238);Gain of ubiquitination at Q314 (P = 0.0238);
MVP		0.96
MPC		0.013
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.51
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Pathogenic	0.78
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: rs1114167845; hg19: chr2-47641555; COSMIC: COSV105085992; COSMIC: COSV105085992;