NM_000251.3(MSH2):c.126C>G (p.Phe42Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000212577.8

Allele description [Variation Report for NM_000251.3(MSH2):c.126C>G (p.Phe42Leu)]

NM_000251.3(MSH2):c.126C>G (p.Phe42Leu)

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.126C>G (p.Phe42Leu)

Other names:

p.F42L:TTC>TTG

HGVS:

NC_000002.12:g.47403317C>G
NG_007110.2:g.5194C>G
NM_000251.3:c.126C>GMANE SELECT
NM_001258281.1:c.-30-43C>G
NP_000242.1:p.Phe42Leu
NP_000242.1:p.Phe42Leu
LRG_218t1:c.126C>G
LRG_218:g.5194C>G
LRG_218p1:p.Phe42Leu
NC_000002.11:g.47630456C>G
NM_000251.1:c.126C>G
NM_000251.2:c.126C>G
p.F42L

Protein change:

F42L

Links:

dbSNP: rs730881766

NCBI 1000 Genomes Browser:

rs730881766

Molecular consequence:

NM_001258281.1:c.-30-43C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.126C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211201	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 19, 2023)	germline	clinical testing	Citation Link,
SCV004220941	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 16, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25186627, 33471991, 35358259, 33357406, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211201

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 19, 2023)

germline

clinical testing

Citation Link,

SCV004220941

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jun 16, 2023)

unknown

clinical testing

PubMed (5)
[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	germline	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

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000211201.18

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

Description

Observed in at least one individual with breast cancer (PMID: 25186627); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest no damaging effect: performed similar to wild type in an assay measuring resistance to 6-TG (PMID: 33357406); 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: 18822302, 21120944, 25186627, 33357406)

#	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, SCV004220941.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)) and as a somatic variant in a tumor sample from an individual with esophageal cancer (PMID: 35358259 (2022)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in an unaffected control individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Additionally, a functional study shows no damaging effect on protein function ((PMID: 33357406 (2021)), however, further studies assessing the variant's full functional impact are needed. The frequency of this variant in the general population, 0.0000044 (1/229070 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 deleterious or benign. 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: Nov 30, 2024

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