NM_000251.3(MSH2):c.2354A>C (p.His785Pro) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 19, 2021
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:: RCV000522265.7

Allele description [Variation Report for NM_000251.3(MSH2):c.2354A>C (p.His785Pro)]

NM_000251.3(MSH2):c.2354A>C (p.His785Pro)

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.2354A>C (p.His785Pro)

HGVS:

NC_000002.12:g.47478415A>C
NG_007110.2:g.80292A>C
NM_000251.3:c.2354A>CMANE SELECT
NM_001258281.1:c.2156A>C
NP_000242.1:p.His785Pro
NP_000242.1:p.His785Pro
NP_001245210.1:p.His719Pro
LRG_218t1:c.2354A>C
LRG_218:g.80292A>C
LRG_218p1:p.His785Pro
NC_000002.11:g.47705554A>C
NM_000251.1:c.2354A>C
NM_000251.2:c.2354A>C
p.H785P

Protein change:

H719P

Links:

dbSNP: rs200252727

NCBI 1000 Genomes Browser:

rs200252727

Molecular consequence:

NM_000251.3:c.2354A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2156A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696245	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 19, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 25559809, 31569399, 30798936 Citation Link,
SCV000712626	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Nov 17, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25559809, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696245

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 19, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000712626

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Nov 17, 2016)

germline

clinical testing

PubMed (2)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	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

Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women.

Wu B, Peng Y, Eggert J, Alexov E.

Int J Mol Sci. 2019 Sep 28;20(19). doi:pii: E4828. 10.3390/ijms20194828.

PubMed [citation]

PMID:: 31569399
PMCID:: PMC6801521

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696245.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: MSH2 c.2354A>C (p.His785Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251450 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2354A>C has been reported in the literature in individuals affected with colon cancer and breast cancer (example, Chubb_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been reported (Chubb_2015, POLD1 c.1433G>A, p.Ser478Asn), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712626.1

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

Description

The p.His785Pro variant in MSH2 has been reported in 1 individual with colorecta l cancer; however, this patient also harbored a likely disease causing variant i n the POLD1 gene (Chubb et al 2015; POLD1, Ser478Asn: Palles 2013). The His785Pr o variant has been identified in 2/66730 European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200252727). Com putational prediction tools and conservation analysis suggest that the p.His785P ro variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.H is785Pro variant is uncertain.

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

Last Updated: Oct 13, 2024

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