2-189805813-TA-T

Variant names:

• chr2-189805813-TA-T
• rs3214425
• NM_000534.5:c.418+70delA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_001321049.2(PMS1):​c.488delA​(p.Lys163SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,231,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0066 (0 hom.)
• Consequence: PMS1 NM_001321049.2 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.609

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-189805813-TA-T is Benign according to our data. Variant chr2-189805813-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 3058885.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00655 (7093/1082844) while in subpopulation AMR AF= 0.0207 (646/31188). AF 95% confidence interval is 0.0194. There are 0 homozygotes in gnomad4_exome. There are 3798 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.418+70delA		intron_variant	Intron 4 of 12	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.418+70delA		intron_variant	Intron 4 of 12	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 21 AN: 148822 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00655 AC: 7093 AN: 1082844 Hom.: 0 Cov.: 31 AF XY: 0.00710 AC XY: 3798 AN XY: 534708

Gnomad4 AFR exome AF: 0.00658

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.00911

Gnomad4 EAS exome AF: 0.00712

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.00707

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.000148 AC: 22 AN: 148912 Hom.: 0 Cov.: 25 AF XY: 0.000179 AC XY: 13 AN XY: 72592

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.000201

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000510

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PMS1-related disorder Benign:1

Oct 21, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs3214425; hg19: chr2-190670539;