7-5973385-T-C

Variant names:

• chr7-5973385-T-C
• rs1057520349
• NM_000535.7:c.*14A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000535.7(PMS2):​c.*14A>G variant causes a 3 prime UTR 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000083 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.72

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-5973385-T-C is Benign according to our data. Variant chr7-5973385-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 378391.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.*14A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.*14A>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00000829 AC: 1 AN: 120628 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000177

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000122 AC: 9 AN: 734698 Hom.: 0 Cov.: 9 AF XY: 0.00000518 AC XY: 2 AN XY: 386048

⚠️ 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: 19068

American (AMR) AF: 0.00 AC: 0 AN: 33568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19666

East Asian (EAS) AF: 0.00 AC: 0 AN: 30854

South Asian (SAS) AF: 0.00 AC: 0 AN: 63098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2928

European-Non Finnish (NFE) AF: 0.0000186 AC: 9 AN: 484316

Other (OTH) AF: 0.00 AC: 0 AN: 35052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000057), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000829 AC: 1 AN: 120628 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 57790

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

African (AFR) AF: 0.00 AC: 0 AN: 31854

American (AMR) AF: 0.00 AC: 0 AN: 11452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2948

East Asian (EAS) AF: 0.00 AC: 0 AN: 3778

South Asian (SAS) AF: 0.00 AC: 0 AN: 3392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000177 AC: 1 AN: 56442

Other (OTH) AF: 0.00 AC: 0 AN: 1586

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 03, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.7

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

Publications

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Other links and lift over

dbSNP: rs1057520349; hg19: chr7-6013016;