NM_000535.7(PMS2):c.1642G>A (p.Asp548Asn) AND Hereditary nonpolyposis colon cancer

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 25, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000195742.2

Allele description

NM_000535.7(PMS2):c.1642G>A (p.Asp548Asn)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.1642G>A (p.Asp548Asn)

HGVS:

NC_000007.14:g.5987123C>T
NG_008466.1:g.26984G>A
NM_000535.7:c.1642G>A
NP_000526.2:p.Asp548Asn
LRG_161t1:c.1642G>A
LRG_161:g.26984G>A
LRG_161p1:p.Asp548Asn
NC_000007.13:g.6026754C>T
NM_000535.5:c.1642G>A
NM_000535.6:c.1642G>A
NP_000526.1:p.Asp548Asn
NR_136154.1:n.1729G>A

Protein change:

D548N

Links:

dbSNP: rs374591423

Molecular consequence:

NM_000535.6:c.1642G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1729G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer
Identifiers:: MedGen: C0009405; Orphanet: 443090

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254603	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Uncertain significance (Nov 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254603

Invitae

criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))

Uncertain significance
(Nov 25, 2017)

germline

clinical testing

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

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000254603.3

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

Description

This sequence change replaces aspartic acid with asparagine at codon 548 of the PMS2 protein (p.Asp548Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs374591423, ExAC 0.003%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 216453). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

Last Updated: May 20, 2019

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