2-189795957-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000534.5(PMS1):c.315+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,578,098 control chromosomes in the GnomAD database, including 1,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (113 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1123 hom.)
• Consequence: PMS1 NM_000534.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001624
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.470

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-189795957-G-A is Benign according to our data. Variant chr2-189795957-G-A is described in ClinVar as [Benign]. Clinvar id is 1274521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.315+6G>A		splice_donor_region_variant, intron_variant		ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.315+6G>A		splice_donor_region_variant, intron_variant		1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4727 AN: 152130 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0340 AC: 8538 AN: 250968 Hom.: 218 AF XY: 0.0326 AC XY: 4426 AN XY: 135756

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0357 AC: 50856 AN: 1425850 Hom.: 1123 Cov.: 25 AF XY: 0.0350 AC XY: 24893 AN XY: 711716

Gnomad4 AFR exome AF: 0.00589

Gnomad4 AMR exome AF: 0.0542

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.000632

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0734

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0310 AC: 4724 AN: 152248 Hom.: 113 Cov.: 32 AF XY: 0.0322 AC XY: 2396 AN XY: 74446

Gnomad4 AFR AF: 0.00727

Gnomad4 AMR AF: 0.0562

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0380

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0331 Hom.: 53

Bravo AF: 0.0273

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0324

EpiControl AF: 0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	13
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.014
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: rs5742981; hg19: chr2-190660683;