2-189805832-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000534.5(PMS1):c.418+78G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,582,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -1.25

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010663331).
• BP6: Variant 2-189805832-G-A is Benign according to our data. Variant chr2-189805832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133375.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.418+78G>A		intron_variant		ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.418+78G>A		intron_variant		1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.000560 AC: 85 AN: 151698 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000291 AC: 58 AN: 199036 Hom.: 2 AF XY: 0.000261 AC XY: 28 AN XY: 107414

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.000732

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.000775

GnomAD4 exome AF: 0.000237 AC: 339 AN: 1430564 Hom.: 2 Cov.: 33 AF XY: 0.000268 AC XY: 190 AN XY: 709074

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.000656

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000386

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000542

GnomAD4 genome AF: 0.000567 AC: 86 AN: 151808 Hom.: 0 Cov.: 33 AF XY: 0.000553 AC XY: 41 AN XY: 74178

Gnomad4 AFR AF: 0.00138

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000955

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000535 Hom.: 2

Bravo AF: 0.000684

ExAC AF: 0.000269 AC: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

PMS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2022

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). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	1.9
Dann	Benign	0.84
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	1.3	N
REVEL	Benign	0.13
Sift	Benign	0.46	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.066
MVP		0.85
ClinPred		0.0019	T
GERP RS		0.32

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: rs550407834; hg19: chr2-190670558;