2-189817906-G-C

Variant names:

• chr2-189817906-G-C
• rs3791773
• NM_000534.5:c.419-111G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. 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
	PMS1	NM_000534.5	MANE Select	c.419-111G>C		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.419-111G>C		intron	N/A	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.419-111G>C		intron	N/A	NP_001307976.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.419-111G>C		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000424059.1	TSL:1	n.419-111G>C		intron	N/A
	PMS1	ENST00000921104.1		c.419-111G>C		intron	N/A	ENSP00000591163.1

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

African (AFR) AF: 0.292 AC: 5117 AN: 17540

American (AMR) AF: 0.230 AC: 7719 AN: 33624

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 4249 AN: 19870

East Asian (EAS) AF: 0.227 AC: 7543 AN: 33176

South Asian (SAS) AF: 0.118 AC: 7662 AN: 64780

European-Finnish (FIN) AF: 0.200 AC: 9135 AN: 45788

Middle Eastern (MID) AF: 0.230 AC: 579 AN: 2512

European-Non Finnish (NFE) AF: 0.197 AC: 77358 AN: 393526

Other (OTH) AF: 0.202 AC: 6510 AN: 32210

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

African (AFR) AF: 0.284 AC: 11751 AN: 41440

American (AMR) AF: 0.249 AC: 3809 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3466

East Asian (EAS) AF: 0.227 AC: 1170 AN: 5160

South Asian (SAS) AF: 0.120 AC: 576 AN: 4814

European-Finnish (FIN) AF: 0.196 AC: 2065 AN: 10562

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13363 AN: 67972

Other (OTH) AF: 0.217 AC: 458 AN: 2108

Alfa AF: 0.127 Hom.: 230

Bravo AF: 0.231

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.47
PhyloP100		0.76
PromoterAI		-0.0059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3791773; hg19: chr2-190682632;