7-5973397-G-C

Variant names:

• chr7-5973397-G-C
• rs764124442
• ENST00000406569.8:n.*232C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000406569.8(PMS2):​n.*232C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 ENST00000406569.8 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.60
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-5973397-G-C is Benign according to our data. Variant chr7-5973397-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2774116.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406569.8. 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.*2C>G		3_prime_UTR	Exon 15 of 15	NP_000526.2
	PMS2	NR_136154.1		n.2635C>G		non_coding_transcript_exon	Exon 15 of 15
	PMS2	NM_001406866.1		c.*2C>G		3_prime_UTR	Exon 16 of 16	NP_001393795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000406569.8	TSL:1	n.*232C>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.*2C>G		3_prime_UTR	Exon 15 of 15	ENSP00000265849.7
	PMS2	ENST00000406569.8	TSL:1	n.*232C>G		3_prime_UTR	Exon 13 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD2 exomes AF: 0.00000501 AC: 1 AN: 199490 AF XY: 0.00000921

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000485 AC: 4 AN: 824220 Hom.: 0 Cov.: 11 AF XY: 0.00000467 AC XY: 2 AN XY: 428384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20774

American (AMR) AF: 0.00 AC: 0 AN: 35570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20392

East Asian (EAS) AF: 0.000128 AC: 4 AN: 31150

South Asian (SAS) AF: 0.00 AC: 0 AN: 65954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 563230

Other (OTH) AF: 0.00 AC: 0 AN: 37990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 19

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 3' untranslated region of the PMS2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/199490 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.

Lynch syndrome 4 Benign:1

Feb 04, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant occurs in the non-coding 3' untranslated region of the gene, and is not expected to impact protein function.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0050
DANN	Benign	0.58
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs764124442; hg19: chr7-6013028;