rs1145232

Positions:

• chr2-189854773-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000534.5(PMS1):​c.1501G>A​(p.Gly501Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,613,614 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (33 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 6.02

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]

LOC105373796 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004475683).
• BP6: Variant 2-189854773-G-A is Benign according to our data. Variant chr2-189854773-G-A is described in ClinVar as [Benign]. Clinvar id is 135054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1975/152132) while in subpopulation AFR AF= 0.0445 (1847/41494). AF 95% confidence interval is 0.0428. There are 37 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.1501G>A	p.Gly501Arg	missense_variant	9/13	ENST00000441310.7
LOC105373796	XR_001739151.2	n.319-1916C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.1501G>A	p.Gly501Arg	missense_variant	9/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1962 AN: 152014 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00379 AC: 947 AN: 249904 Hom.: 15 AF XY: 0.00306 AC XY: 415 AN XY: 135506

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000584

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00163 AC: 2389 AN: 1461482 Hom.: 33 Cov.: 31 AF XY: 0.00145 AC XY: 1054 AN XY: 727050

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00412

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0130 AC: 1975 AN: 152132 Hom.: 37 Cov.: 32 AF XY: 0.0127 AC XY: 946 AN XY: 74374

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00240 Hom.: 11

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0417 AC: 183

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00435 AC: 528

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

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
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;T;T;T;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;D;D;T;D
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.2	.;.;D;.;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;D;.;.;.;.
Vest4		0.48, 0.48, 0.52, 0.44, 0.48, 0.47
MutPred		0.73		.;.;.;.;Loss of helix (P = 0.0072);.;Loss of helix (P = 0.0072);.;.;
MVP		1.0
MPC		0.28
ClinPred		0.041	T
GERP RS		4.8
Varity_R		0.85
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1145232; hg19: chr2-190719499; COSMIC: COSV99066312; COSMIC: COSV99066312;