2-189818173-A-C

Variant names:

• chr2-189818173-A-C
• rs587778610
• NM_000534.5:c.575A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000534.5(PMS1):​c.575A>C​(p.His192Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H192R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.18
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.575A>C	p.His192Pro	missense_variant	Exon 5 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.575A>C	p.His192Pro	missense_variant	Exon 5 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426622 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 711786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32784

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 85310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081096

Other (OTH) AF: 0.00 AC: 0 AN: 59122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;T;T;T;T;.;T;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;D;T;T;D;T;T;D;D;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.9	.;.;.;.;.;M;M;.;M;.;.
PhyloP100		8.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.0	.;.;D;.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	.;.;D;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	.;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;.;.;D;D;D;.;.;.;.;.
Vest4		0.93, 0.92, 0.89, 0.83, 0.89, 0.88, 0.90
MutPred		0.58		Loss of catalytic residue at N193 (P = 0.0553);.;.;Loss of catalytic residue at N193 (P = 0.0553);Loss of catalytic residue at N193 (P = 0.0553);Loss of catalytic residue at N193 (P = 0.0553);Loss of catalytic residue at N193 (P = 0.0553);Loss of catalytic residue at N193 (P = 0.0553);Loss of catalytic residue at N193 (P = 0.0553);.;.;
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.0052	Neutral
Varity_R		0.93
gMVP		0.83
Mutation Taster		=21/79	disease causing

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: rs587778610; hg19: chr2-190682899;