2-189817906-G-C

Position:

• chr2-189817906-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000534.5(PMS1):​c.419-111G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 795,032 control chromosomes in the GnomAD database, including 17,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4035 hom., cov: 32)
  • Exomes 𝑓: 0.20 (13066 hom.)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.758

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-189817906-G-C is Benign according to our data. Variant chr2-189817906-G-C is described in ClinVar as [Benign]. Clinvar id is 1283805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.419-111G>C		intron_variant		ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.419-111G>C		intron_variant		1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34118 AN: 151888 Hom.: 4027 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.196 AC: 125872 AN: 643026 Hom.: 13066 AF XY: 0.192 AC XY: 65718 AN XY: 343006

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.225 AC: 34145 AN: 152006 Hom.: 4035 Cov.: 32 AF XY: 0.222 AC XY: 16516 AN XY: 74286

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.217

Alfa AF: 0.127 Hom.: 230

Bravo AF: 0.231

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.47

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: rs3791773; hg19: chr2-190682632;