Genetic Variant MSH2:c.-100G>A (chr2-47403092-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001258281.1(MSH2):c.-114G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,117,360 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

MSH2
NM_001258281.1 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258281.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH2	NM_001258281.1		c.-114G>A	5_prime_UTR	Exon 1 of 17	NP_001245210.1	P43246-2
MSH2	NM_000251.3	MANE Select	c.-100G>A	upstream_gene	N/A	NP_000242.1	P43246-1
MSH2	NM_001406674.1		c.-100G>A	upstream_gene	N/A	NP_001393603.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH2	ENST00000946816.1		c.-100G>A	5_prime_UTR	Exon 1 of 17	ENSP00000616875.1
MSH2	ENST00000910409.1		c.-100G>A	5_prime_UTR	Exon 1 of 16	ENSP00000580468.1
MSH2	ENST00000543555.6	TSL:2	c.-114G>A	5_prime_UTR	Exon 1 of 17	ENSP00000442697.1	P43246-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000179

AC:

AN:

1117360

Hom.:

Cov.:

AF XY:

0.00000178

AC XY:

AN XY:

562676

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26230

American (AMR)

AF:

0.00

AC:

AN:

35370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23540

East Asian (EAS)

AF:

0.00

AC:

AN:

34482

South Asian (SAS)

AF:

0.00

AC:

AN:

73544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3610

European-Non Finnish (NFE)

AF:

0.00000239

AC:

AN:

837468

Other (OTH)

AF:

0.00

AC:

AN:

49068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.1

PromoterAI

0.17

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over