rs5742981

Variant names:

• chr2-189795957-G-A
• rs5742981
• NM_000534.5:c.315+6G>A

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.315+6G>A variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0001624
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.470
• Publications: 7 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=-0.66).
• BP6: Variant 2-189795957-G-A is Benign according to our data. Variant chr2-189795957-G-A is described in ClinVar as Benign. ClinVar VariationId is 1274521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.315+6G>A		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.315+6G>A		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_000534.5	ENSP00000406490.3

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

GnomAD2 exomes AF: 0.0340 AC: 8538 AN: 250968 AF XY: 0.0326

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 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

African (AFR) AF: 0.00589 AC: 193 AN: 32744

American (AMR) AF: 0.0542 AC: 2422 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 303 AN: 25896

East Asian (EAS) AF: 0.000632 AC: 25 AN: 39538

South Asian (SAS) AF: 0.0127 AC: 1084 AN: 85538

European-Finnish (FIN) AF: 0.0734 AC: 3917 AN: 53400

Middle Eastern (MID) AF: 0.00299 AC: 17 AN: 5692

European-Non Finnish (NFE) AF: 0.0381 AC: 41162 AN: 1079198

Other (OTH) AF: 0.0293 AC: 1733 AN: 59170

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

African (AFR) AF: 0.00727 AC: 302 AN: 41552

American (AMR) AF: 0.0562 AC: 860 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4822

European-Finnish (FIN) AF: 0.0741 AC: 785 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0380 AC: 2583 AN: 68002

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.0344 Hom.: 92

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5742981; hg19: chr2-190660683;