2-47403214-C-T

Variant names:

• chr2-47403214-C-T
• rs17217716
• NM_000251.3:c.23C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406654.1(MSH2):​c.-318C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,600,010 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (10 hom.)
• Consequence: MSH2 NM_001406654.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:1 B:26 O:1
• Conservation: PhyloP100: 2.77
• Publications: 39 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007815033).
• BP6: Variant 2-47403214-C-T is Benign according to our data. Variant chr2-47403214-C-T is described in ClinVar as Benign. ClinVar VariationId is 90964.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00208 (317/152366) while in subpopulation AMR AF = 0.0142 (217/15306). AF 95% confidence interval is 0.0126. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406654.1. 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.23C>T	p.Thr8Met	missense	Exon 1 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406654.1		c.-318C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001393583.1
	MSH2	NM_001406656.1		c.-973C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001393585.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.23C>T	p.Thr8Met	missense	Exon 1 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.23C>T	p.Thr8Met	missense	Exon 1 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.23C>T	p.Thr8Met	missense	Exon 1 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152248 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00303 AC: 674 AN: 222448 AF XY: 0.00255

Gnomad AFR exome AF: 0.000225

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.000747

Gnomad EAS exome AF: 0.00653

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.000980 AC: 1418 AN: 1447644 Hom.: 10 Cov.: 31 AF XY: 0.000963 AC XY: 692 AN XY: 718930

African (AFR) AF: 0.000150 AC: 5 AN: 33332

American (AMR) AF: 0.0145 AC: 617 AN: 42426

Ashkenazi Jewish (ASJ) AF: 0.000427 AC: 11 AN: 25774

East Asian (EAS) AF: 0.0112 AC: 439 AN: 39202

South Asian (SAS) AF: 0.00112 AC: 94 AN: 83946

European-Finnish (FIN) AF: 0.00132 AC: 67 AN: 50880

Middle Eastern (MID) AF: 0.000356 AC: 2 AN: 5622

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1106626

Other (OTH) AF: 0.00119 AC: 71 AN: 59836

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152366 Hom.: 2 Cov.: 33 AF XY: 0.00274 AC XY: 204 AN XY: 74510

African (AFR) AF: 0.000216 AC: 9 AN: 41592

American (AMR) AF: 0.0142 AC: 217 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000873 Hom.: 1

Bravo AF: 0.00252

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00182 AC: 219

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	1	4	Lynch syndrome 1 (5)
-	-	4	not provided (4)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.57
Sift	Benign	0.087	T
Sift4G	Benign	0.10	T
Polyphen		0.83	P
Vest4		0.17
MVP		0.98
MPC		0.0065
ClinPred		0.061	T
GERP RS		4.4
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.082
gMVP		0.37
Mutation Taster		=99/1	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: rs17217716; hg19: chr2-47630353;