rs772662439

chr2-47476558-G-Achr2-47476558-G-Cchr2-47476558-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000251.3(MSH2):c.2197G>A(p.Ala733Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,108 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A733D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:3
• Conservation: PhyloP100: 6.41

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000251.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2197G>A	p.Ala733Thr	missense_variant	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2197G>A	p.Ala733Thr	missense_variant	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152148 Hom.: 0 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: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251444 Hom.: 0 AF XY: 0.0000662 AC XY: 9 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: 0.000326

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 17, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2022	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2019	Variant summary: MSH2 c.2197G>A (p.Ala733Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251444 control chromosomes (gnomAD) among individuals of Eastern Asian and South Asian descent. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (4.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2197G>A has been reported in the literature in sequencing studies among individuals with carcinomas of ovarian/fallopian tube/peritoneal origin, medulloblastoma. breast cancer with family history, sporadic TNBC, and even one individual without a diagnosis of Lynch syndrome (Walsh_2011, Trubicka_2017, Kiyozumi_2019, Wang_2019, Yi_2019). These report(s), that are predominantly of Japanese/Chinese origin, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one of these reports the variant showed no-LOH, was MSI-Stable, had a normal IHC MSI panel, and was interpreted as benign (Walsh_2011). Co-occurrences with other pathogenic/likely pathogenic variant(s) have been reported in the literature (BRCA1 c.928C>T, p.Gln310*; MSH6 c.4055_4063dupAATTGCTGA, p.Lys1352_Leu1354dup), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance limited to two publications (Walsh_2011, Trubicka_2017). Based on the additional emerging evidence outlined above, the variant was classified as VUS-possibly benign. -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

MSH2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2023

The MSH2 c.2197G>A variant is predicted to result in the amino acid substitution p.Ala733Thr. This variant has been reported in one patient with pediatric medulloblastoma (Trubicka et al. 2017. PubMed ID: 28376765), three patients with breast and/or ovarian cancer (Table S2, Yi et al. 2019. PubMed ID: 30630526; Table S2, Wang et al. 2019. PubMed ID: 30982232), one patient with either primary ovarian, peritoneal, or fallopian tube carcinoma (Table S4, Walsh et al. 2011. PubMed ID: 22006311), and one patient with an unspecified cancer (Table S1, Kiyozumi et al. 2019. PubMed ID: 31386297). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47703697-G-A) and is interpreted as uncertain in ClinVar by the majority of laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/216350/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22006311, 28376765, 30630526, 30982232, 31386297, 32547938, 28706299, 18822302, 21120944, YangMengyuan2022, 33357406, 34755017, 33471991, 32980694) -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Ala733Thr variant was identified in 3 of 1886 proband chromosomes (frequency: 0.002) from individuals or families with medulloblastoma and hereditary breast and ovarian cancer (Walsh 2011, Trubicka 2017, Wang 2019). The variant was identified in dbSNP (rs772662439) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 3 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 12 of 251,444 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 6 of 18,394 chromosomes (freq: 0.0003), South Asian in 6 of 30,616 chromosomes (freq: 0.0002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European and Other populations. The p.Ala733 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0030	D;D;.;D
Polyphen		0.98	D;.;.;D
Vest4		0.85
MutPred		0.81		Gain of glycosylation at A733 (P = 0.0655);.;Gain of glycosylation at A733 (P = 0.0655);Gain of glycosylation at A733 (P = 0.0655);
MVP		0.92
MPC		0.031
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.93

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: rs772662439; hg19: chr2-47703697; COSMIC: COSV51876328;