rs570998668

Variant names:

• chr7-5997429-A-AC
• rs570998668
• NM_000535.7:c.706-7_706-6insG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_000535.7(PMS2):​c.706-7_706-6insG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,039,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.267
• Publications: 2 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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-5997429-A-AC is Benign according to our data. Variant chr7-5997429-A-AC is described in ClinVar as Likely_benign. ClinVar VariationId is 455736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.706-7_706-6insG		splice_region_variant, intron_variant	Intron 6 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.706-7_706-6insG		splice_region_variant, intron_variant	Intron 6 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.000320 AC: 37 AN: 115778 AF XY: 0.000333

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.000194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000580

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 5 AN: 1039266 Hom.: 0 Cov.: 21 AF XY: 0.00000388 AC XY: 2 AN XY: 515004

African (AFR) AF: 0.00 AC: 0 AN: 23884

American (AMR) AF: 0.00 AC: 0 AN: 31646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17340

East Asian (EAS) AF: 0.00 AC: 0 AN: 23658

South Asian (SAS) AF: 0.0000898 AC: 5 AN: 55672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4158

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 801288

Other (OTH) AF: 0.00 AC: 0 AN: 42204

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Apr 06, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27

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: rs570998668; hg19: chr7-6037060;