NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys) AND Lynch syndrome 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 23, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000409784.6

Allele description [Variation Report for NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys)]

NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys)

Other names:

p.Y43C:TAT>TGT

HGVS:

NC_000002.12:g.47403319A>G
NG_007110.2:g.5196A>G
NM_000251.3:c.128A>GMANE SELECT
NM_001258281.1:c.-30-41A>G
NP_000242.1:p.Tyr43Cys
NP_000242.1:p.Tyr43Cys
LRG_218t1:c.128A>G
LRG_218:g.5196A>G
LRG_218p1:p.Tyr43Cys
NC_000002.11:g.47630458A>G
NM_000251.1:c.128A>G
NM_000251.2:c.128A>G
P43246:p.Tyr43Cys
p.Y43C

Protein change:

Y43C

Links:

UniProtKB: P43246#VAR_019233; dbSNP: rs17217723

NCBI 1000 Genomes Browser:

rs17217723

Molecular consequence:

NM_001258281.1:c.-30-41A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.128A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome 1
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 1; MSH2-Related Hereditary Non-Polyposis Colon Cancer; Lynch syndrome I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007356; MedGen: C2936783; Orphanet: 144; OMIM: 120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488599	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (May 4, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26580448, 26094658, 16395668 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001135690	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001482848	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 23, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004018416	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Detection of novel germline mutations for breast cancer in non-BRCA1/2 families.

Aloraifi F, McDevitt T, Martiniano R, McGreevy J, McLaughlin R, Egan CM, Cody N, Meany M, Kenny E, Green AJ, Bradley DG, Geraghty JG, Bracken AP.

FEBS J. 2015 Sep;282(17):3424-37. doi: 10.1111/febs.13352. Epub 2015 Jul 14.

PubMed [citation]

PMID:: 26094658

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000488599.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001135690.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001482848.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004018416.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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