2-47414370-G-C

Variant names:

• chr2-47414370-G-C
• rs587781397
• NM_000251.3:c.894G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000251.3(MSH2):​c.894G>C​(p.Gln298His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q298R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 28)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 1.78
• Publications: 4 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.894G>C	p.Gln298His	missense	Exon 5 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.894G>C	p.Gln298His	missense	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.894G>C	p.Gln298His	missense	Exon 5 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.894G>C	p.Gln298His	missense	Exon 5 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.894G>C	p.Gln298His	missense	Exon 5 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.945G>C	p.Gln315His	missense	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0000165 AC: 2 AN: 121260 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

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: 0.0000318

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250412 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324222 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 657078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29668

American (AMR) AF: 0.00 AC: 0 AN: 40490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20768

East Asian (EAS) AF: 0.00 AC: 0 AN: 28150

South Asian (SAS) AF: 0.00 AC: 0 AN: 84682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4858

European-Non Finnish (NFE) AF: 9.79e-7 AC: 1 AN: 1021636

Other (OTH) AF: 0.00 AC: 0 AN: 51010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000165 AC: 2 AN: 121260 Hom.: 0 Cov.: 28 AF XY: 0.0000358 AC XY: 2 AN XY: 55878

African (AFR) AF: 0.00 AC: 0 AN: 32302

American (AMR) AF: 0.00 AC: 0 AN: 8842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 3504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.0000318 AC: 2 AN: 62876

Other (OTH) AF: 0.00 AC: 0 AN: 1606

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	Lynch syndrome (2)
-	2	-	Lynch syndrome 1 (2)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.51		Gain of ubiquitination at K301 (P = 0.143)
MVP		0.97
MPC		0.034
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.57
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs587781397; hg19: chr2-47641509;