rs61756468

Positions:

• chr2-47475151-A-G
• chr2-47475151-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000251.3(MSH2):​c.1886A>G​(p.Gln629Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,614,156 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q629E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:18 O:1
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 13 uncertain in NM_000251.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.014180899).
• BP6: Variant 2-47475151-A-G is Benign according to our data. Variant chr2-47475151-A-G is described in ClinVar as [Benign]. Clinvar id is 90812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475151-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000545 (83/152284) while in subpopulation EAS AF= 0.0145 (75/5180). AF 95% confidence interval is 0.0118. There are 1 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1886A>G	p.Gln629Arg	missense_variant	12/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1886A>G	p.Gln629Arg	missense_variant	12/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00120 AC: 303 AN: 251464 Hom.: 0 AF XY: 0.00112 AC XY: 152 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000383 AC: 560 AN: 1461872 Hom.: 4 Cov.: 33 AF XY: 0.000364 AC XY: 265 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0130

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000703

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 1 Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 04, 2017	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2016	Variant summary: The MSH2 c.1886A>G (p.Gln629Arg) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 159/123118 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0174486 (151/8654). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has also been reported in colorectal patients or HNPCC-related cancer without strong evidence for pathogenicity. In a family, while affected proband carried the variant, another affected cousin did not carry the variant, possibly suggesting that it did not co-segregate with disease in the family (Woo_2014). Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 24933000, 22995991, 22283331, 22949387, 29506494, 27487738, 15365995, 21155023, 22290698, 20965939, 23760103, 24728327, 12132870, 26332594, 25985138, 24078570, 29642919, 15996210, 16929514, 18257912, 18383312, 18636359, 18726168, 24396821, 28580595) -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 07, 2022

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Gln629Arg variant was identified in 8 of 882 proband chromosomes (frequency: 0.009) from individuals or families with colon cancer, gastric cancer, and hepatocellular carcinoma (Jin 2008, Lee 2005, Lim 2010, Shin 2004, Wang 2006, Yano 2007, Yap 2009, Zhang 2006). Yuan (2004) also found the variant in 7 of 200 chromosomes in unaffected individuals (freq 0.035), and therefore classified the variant as a polymorphism. The variant was also identified in dbSNP (ID: rs61756468) as “With Uncertain significance allele”, ClinVar (as benign, reviewed by an expert panel), Clinvitae (as benign), Cosmic, Insight Colon Cancer Gene Variant Database (reported 19x as benign), Zhejiang Colon Cancer Database (reported 6x), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, MMR Gene Unclassified Variants Database. The variant was identified in control databases in 317 of 277184 chromosomes at a frequency of 0.0011 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 304 (1 homozygous) of 18870 chromosomes (freq: 0.01611), Other in 2 of 6464 chromosomes (freq: 0.000309), European (Non-Finnish) in 1 of 126690 chromosomes (freq: 0.000008), European (Finnish) in 3 of 25786 chromosomes (freq: 0.000116), and South Asian in 7 of 30782 chromosomes (freq: 0.000227), while the variant was not observed in the African, Latino, or Ashkenazi Jewish populations. The p.Gln629 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.72	T;T;T;T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	L;.;.;.
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Uncertain	0.51
Sift	Benign	0.32	T;T;.;T
Sift4G	Benign	0.12	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.30
MVP		1.0
MPC		0.0064
ClinPred		0.0094	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs61756468; hg19: chr2-47702290; COSMIC: COSV51875543; COSMIC: COSV51875543;