rs55859129

chr2-47482910-T-Cchr2-47482910-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000251.3(MSH2):c.2766T>C(p.Phe922=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,611,950 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (27 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: 0.382

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-47482910-T-C is Benign according to our data. Variant chr2-47482910-T-C is described in ClinVar as [Benign]. Clinvar id is 91042.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47482910-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.382 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1754/152338) while in subpopulation AFR AF= 0.0401 (1668/41570). AF 95% confidence interval is 0.0385. There are 23 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2766T>C	p.Phe922=	synonymous_variant	16/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2766T>C	p.Phe922=	synonymous_variant	16/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1748 AN: 152220 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00303 AC: 752 AN: 248234 Hom.: 10 AF XY: 0.00224 AC XY: 300 AN XY: 134180

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1459612 Hom.: 27 Cov.: 31 AF XY: 0.000960 AC XY: 697 AN XY: 725928

Gnomad4 AFR exome AF: 0.0411

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.0115 AC: 1754 AN: 152338 Hom.: 23 Cov.: 33 AF XY: 0.0115 AC XY: 854 AN XY: 74490

Gnomad4 AFR AF: 0.0401

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00274 Hom.: 8

Bravo AF: 0.0132

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

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	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -

Lynch syndrome 1 Benign:3

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 10, 2014	MAF >1% -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Phe922= variant was identified in 1 of 70 proband chromosomes (frequency: 0.01) from Portuguese individuals or families with HNPCC and was not identified in 400 control chromosomes from healthy individuals (Isidro_2003_14517962). In addition, mRNA analysis showed the variant yielded no alternative transcripts, and segregation studies showed the variant was found in both affected and unaffected family members (Isidro_2003_14517962). The variant was also identified in dbSNP (ID: rs55859129) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (2014); submitters: benign by InSIGHT, Invitae, Ambry Genetics and Mayo Clinic, and likely benign by Illumina), Clinvitae (4x), UMD-LSDB (4x as neutral, co-occurring with a pathogenic MSH6 variant (c.2150_2153delTCAG (p.Val717AlafsX18)), Insight Colon Cancer Gene Variant Database (3x as class 1), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database, and was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1074 (14 homozygous) of 274470 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 989 (14 homozygous) of 23868 chromosomes (freq: 0.04), Other in 7 of 6412 chromosomes (freq: 0.001), Latino in 71 of 34118 chromosomes (freq: 0.002), European Non-Finnish in 7 of 125698 chromosomes (freq: 0.00006), while not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Phe922= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.6
Dann	Benign	0.77

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: rs55859129; hg19: chr2-47710049; COSMIC: COSV104575372;