NM_000251.3(MSH2):c.174C>A (p.Phe58Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 20, 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:: RCV000568410.10

Allele description [Variation Report for NM_000251.3(MSH2):c.174C>A (p.Phe58Leu)]

NM_000251.3(MSH2):c.174C>A (p.Phe58Leu)

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.174C>A (p.Phe58Leu)

HGVS:

NC_000002.12:g.47403365C>A
NG_007110.2:g.5242C>A
NM_000251.3:c.174C>AMANE SELECT
NM_001258281.1:c.-25C>A
NP_000242.1:p.Phe58Leu
NP_000242.1:p.Phe58Leu
LRG_218t1:c.174C>A
LRG_218:g.5242C>A
LRG_218p1:p.Phe58Leu
NC_000002.11:g.47630504C>A
NM_000251.1:c.174C>A
NM_000251.2:c.174C>A

Protein change:

F58L

Links:

dbSNP: rs372189599

NCBI 1000 Genomes Browser:

rs372189599

Molecular consequence:

NM_001258281.1:c.-25C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000251.3:c.174C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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Notropis suttkusi cytochrome c oxidase subunit I (COI) gene, partial cds; mitoch...
Notropis suttkusi cytochrome c oxidase subunit I (COI) gene, partial cds; mitochondrial gene for mitochondrial product
gi|21748107|gb|AY116186.1|

Nucleotide
cytochrome oxidase subunit 1, partial (mitochondrion) [Xiphophorus maculatus]
cytochrome oxidase subunit 1, partial (mitochondrion) [Xiphophorus maculatus]
gi|189165423|gb|ACD77926.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000669807	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33357406, 33471991 Citation Link,
SCV000908271	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 13, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534405	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 3, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669807

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 20, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000908271

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 13, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002534405

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 3, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]

PMID:: 33357406
PMCID:: PMC7820803

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 (3)

Details of each submission

From Ambry Genetics, SCV000669807.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely 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.

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

From Color Diagnostics, LLC DBA Color Health, SCV000908271.2

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

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

From Sema4, Sema4, SCV002534405.1

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

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

Last Updated: Oct 26, 2024

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