NM_000251.3(MSH2):c.138C>G (p.His46Gln) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 26, 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:: RCV001719811.12

Allele description [Variation Report for NM_000251.3(MSH2):c.138C>G (p.His46Gln)]

NM_000251.3(MSH2):c.138C>G (p.His46Gln)

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.138C>G (p.His46Gln)

Other names:

p.H46Q:CAC>CAG

HGVS:

NC_000002.12:g.47403329C>G
NG_007110.2:g.5206C>G
NM_000251.3:c.138C>GMANE SELECT
NM_001258281.1:c.-30-31C>G
NP_000242.1:p.His46Gln
NP_000242.1:p.His46Gln
LRG_218t1:c.138C>G
LRG_218:g.5206C>G
LRG_218p1:p.His46Gln
NC_000002.11:g.47630468C>G
NM_000251.1:c.138C>G
NM_000251.2:c.138C>G
P43246:p.His46Gln
p.H46Q

Protein change:

H46Q

Links:

UniProtKB: P43246#VAR_004470; dbSNP: rs33946261

NCBI 1000 Genomes Browser:

rs33946261

Molecular consequence:

NM_001258281.1:c.-30-31C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.138C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149410	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Apr 14, 2021)	germline	clinical testing	Citation Link,
SCV004220947	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Apr 26, 2023)	unknown	clinical testing	PubMed (29) [See all records that cite these PMIDs] 27153395, 28195393, 28874130, 33471991, 31297992, 30374176, 29368341, 15520370, 8700523, 26333163, 9259192, 19389263, 26951660, 35264596, 15872200, 26344056, 27601186, 23047549, 24728327, 18033691, 18383312, 25637381, 29212164, 34117267, 33580181, 33357406, 31391288, 29945567, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149410

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Apr 14, 2021)

germline

clinical testing

Citation Link,

SCV004220947

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Apr 26, 2023)

unknown

clinical testing

PubMed (29)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.

Maxwell KN, Hart SN, Vijai J, Schrader KA, Slavin TP, Thomas T, Wubbenhorst B, Ravichandran V, Moore RM, Hu C, Guidugli L, Wenz B, Domchek SM, Robson ME, Szabo C, Neuhausen SL, Weitzel JN, Offit K, Couch FJ, Nathanson KL.

Am J Hum Genet. 2016 May 5;98(5):801-817. doi: 10.1016/j.ajhg.2016.02.024.

PubMed [citation]

PMID:: 27153395
PMCID:: PMC4863474

Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.

Hansen MF, Johansen J, Sylvander AE, Bjørnevoll I, Talseth-Palmer BA, Lavik LAS, Xavier A, Engebretsen LF, Scott RJ, Drabløs F, Sjursen W.

Clin Genet. 2017 Oct;92(4):405-414. doi: 10.1111/cge.12994. Epub 2017 Mar 22.

PubMed [citation]

PMID:: 28195393

See all PubMed Citations (29)

Details of each submission

From GeneDx, SCV000149410.14

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

Description

This variant is associated with the following publications: (PMID: 15872200, 27153395, 18383312, 24728327, 25637381, 23047549, 19389263, 15520370, 16741161, 18033691, 27601186, 28195393, 26333163, 26344056, 29212164, 28330790, 28125075, 28874130, 24055113, 25479140, 26951660, 29368341, 30374176, 31297992)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220947.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (29)

Description

In the published literature, this variant has been reported in individuals with colorectal cancer and/or multiple adenomatous polyps (PMIDs: 15520370 (2004), 18033691 (2008), 28195393 (2017), 29212164 (2017)), ovarian cancer (PMID: 23047549 (2012)), breast cancer (PMIDs: 27153395 (2016), 29212164 (2017), 33471991 (2021), 35264596 (2022)), pancreatic cancer (PMID: 29945567 (2018)), and gliosarcomas (PMID: 33580181 (2021)). The variant has also been reported in unaffected individuals (PMIDs: 25637381 (2015), 33471991 (2021), 34117267 (2021)). Functional studies have conflicting reports as to whether the variant impacts MSH2 protein expression, stability, and repair (PMIDs: 1587220 (2005), 18033691 (2008), 26344056 (2015), 26344056 (2015), 26951660 (2016), 29212164 (2017), 33357406 (2021)). The frequency of this variant in the general population, 0.00073 (35/47650 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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: Oct 13, 2024

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