NM_000251.3(MSH2):c.2319G>C (p.Lys773Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 5, 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:: RCV001015167.8

Allele description [Variation Report for NM_000251.3(MSH2):c.2319G>C (p.Lys773Asn)]

NM_000251.3(MSH2):c.2319G>C (p.Lys773Asn)

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.2319G>C (p.Lys773Asn)

HGVS:

NC_000002.12:g.47478380G>C
NG_007110.2:g.80257G>C
NM_000251.3:c.2319G>CMANE SELECT
NM_001258281.1:c.2121G>C
NP_000242.1:p.Lys773Asn
NP_000242.1:p.Lys773Asn
NP_001245210.1:p.Lys707Asn
LRG_218t1:c.2319G>C
LRG_218:g.80257G>C
LRG_218p1:p.Lys773Asn
NC_000002.11:g.47705519G>C
NM_000251.1:c.2319G>C
NM_000251.2:c.2319G>C

Protein change:

K707N

Links:

dbSNP: rs745528772

NCBI 1000 Genomes Browser:

rs745528772

Molecular consequence:

NM_000251.3:c.2319G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2121G>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001175975	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001357243	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32447321, 25741868
SCV002534467	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 12, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001175975

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 9, 2022)

germline

clinical testing

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

Citation Link,

SCV001357243

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 5, 2023)

germline

clinical testing

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

SCV002534467

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 12, 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

Integrated case-control and somatic-germline interaction analyses of soft-tissue sarcoma.

Hu F, Yu Y, Chen JS, Hu H, Scheet P, Huff CD.

J Med Genet. 2021 Mar;58(3):145-153. doi: 10.1136/jmedgenet-2019-106814. Epub 2020 May 23.

PubMed [citation]

PMID:: 32447321

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001175975.4

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

Description

The p.K773N variant (also known as c.2319G>C), located in coding exon 14 of the MSH2 gene, results from a G to C substitution at nucleotide position 2319. The lysine at codon 773 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001357243.2

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

Description

This missense variant replaces lysine with asparagine at codon 773 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with soft-tissue sarcoma (PMID: 32447321). This variant has been identified in 2/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of 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 Sema4, Sema4, SCV002534467.1

#	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: Sep 29, 2024

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