NM_000535.7:c.1714_1717delGCAAinsACAT

Variant names:

• chr7-5987048-TTGC-ATGT
• rs1060503126
• NM_000535.7:c.1714_1717delGCAAinsACAT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000535.7(PMS2):​c.1714_1717delGCAAinsACAT​(p.AlaThr572ThrSer) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A572A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.910
• Publications: 1 publications found

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 43 uncertain in NM_000535.7

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.1714_1717delGCAAinsACAT	p.AlaThr572ThrSer	missense	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.1900_1903delGCAAinsACAT	p.AlaThr634ThrSer	missense	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.1714_1717delGCAAinsACAT	p.AlaThr572ThrSer	missense	N/A	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.1714_1717delGCAAinsACAT	p.AlaThr572ThrSer	missense	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.804-4060_804-4057delGCAAinsACAT		intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1678+36_1678+39delGCAAinsACAT		intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Uncertain:2

Nov 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jan 10, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.1714_1717delinsACAT (p.Ala572_Thr573delinsThrSer) results in an in-frame deletion-insertion that is predicted to delete/insert 2 amino acids from the protein. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. Nevertheless, the constituent variants of this deletion-insertion variant (i.e. c.1714G>A/p.Ala572Thr and c.1717A>T/p.Thr573Ser), are found to co-occur (and are likely part of the same haplotype) in at least some individuals in gnomAD v2.1.1, with the allele frequency being lower than the estimated maximal expected allele frequency for pathogenic variant in PMS2 causing Lynch Syncdrome phenotype (0.00011). However, control population data need to be cautiously considered since the variants lie within a region of the PMS2 gene that has high pseudogene homology. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1714G>A and c.1717A>T have been reported to co-occur in one individual affected with Lynch Syndrome (Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

not provided Uncertain:1

Apr 25, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 2 amino acids that are replaced by 2 different amino acids in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; Reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch-related cancer and/or polyps (PMID: 25980754); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17016615, 25980754)

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060503126; hg19: chr7-6026679;