rs587779968

Variant names:

• chr2-47482942-C-G
• rs587779968
• NM_000251.3:c.2798C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47482942-C-G
• chr2-47482942-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000251.3(MSH2):​c.2798C>G​(p.Thr933Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. T933I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.67
• 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1377449).
• BP6: Variant 2-47482942-C-G is Benign according to our data. Variant chr2-47482942-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455585.

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.2798C>G	p.Thr933Ser	missense	Exon 16 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406638.1		c.2837C>G	p.Thr946Ser	missense	Exon 17 of 18	NP_001393567.1
	MSH2	NM_001406641.1		c.2798C>G	p.Thr933Ser	missense	Exon 16 of 17	NP_001393570.1	P43246-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2798C>G	p.Thr933Ser	missense	Exon 16 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2634+2071C>G		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2849C>G	p.Thr950Ser	missense	Exon 17 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1458582 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725456

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5010

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1110946

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.31
Sift	Benign	0.20	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.18		Loss of sheet (P = 0.0483)
MVP		0.87
MPC		0.0067
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.044
gMVP		0.25
Mutation Taster		=92/8	polymorphism

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: rs587779968; hg19: chr2-47710081;