chr7-6009120-T-C

Variant names:

• chr7-6009120-T-C
• rs587779325
• ENST00000699766.1:c.-101A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000699766.1(PMS2):​c.-101A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,286,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PMS2 ENST00000699766.1 5_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.09
• 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]

AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]

AIMP2 Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 17

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000699766.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.-101A>G		upstream_gene	N/A	NP_000526.2	P54278-1
	AIMP2	NM_006303.4	MANE Select	c.-244T>C		upstream_gene	N/A	NP_006294.2
	PMS2	NM_001406866.1		c.-101A>G		upstream_gene	N/A	NP_001393795.1	A0A8V8TNX6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000699766.1		c.-101A>G		5_prime_UTR	Exon 1 of 15	ENSP00000514574.1	A0A8V8TQ50
	PMS2	ENST00000699768.1		c.-101A>G		5_prime_UTR	Exon 1 of 14	ENSP00000514576.1	A0A8V8TQI1
	PMS2	ENST00000699767.1		n.-101A>G		non_coding_transcript_exon	Exon 1 of 15	ENSP00000514575.1	A0A8V8TP89

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1286472 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 648696

African (AFR) AF: 0.00 AC: 0 AN: 29872

American (AMR) AF: 0.00 AC: 0 AN: 43746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.00 AC: 0 AN: 38812

South Asian (SAS) AF: 0.00 AC: 0 AN: 82598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3896

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 955626

Other (OTH) AF: 0.00 AC: 0 AN: 54566

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Lynch syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.0
DANN	Benign	0.70
PhyloP100		-1.1
PromoterAI		-0.020	Neutral

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: rs587779325; hg19: chr7-6048751;