rs151325573
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000534.5(PMS1):c.1609G>A(p.Glu537Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,607,300 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000534.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00207 AC: 314AN: 152020Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00219 AC: 546AN: 249024Hom.: 3 AF XY: 0.00224 AC XY: 302AN XY: 135038
GnomAD4 exome AF: 0.00247 AC: 3591AN: 1455162Hom.: 6 Cov.: 29 AF XY: 0.00244 AC XY: 1764AN XY: 724140
GnomAD4 genome AF: 0.00206 AC: 313AN: 152138Hom.: 1 Cov.: 32 AF XY: 0.00194 AC XY: 144AN XY: 74382
ClinVar
Submissions by phenotype
not provided Benign:2
The PMS1 p.Glu361Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs151325573) and ClinVar (classified as a VUS by Illumina and Genomic Research Center, Shahid Beheshti University of Medical Sciences for Lynch Syndrome). The variant was identified in control databases in 596 of 280400 chromosomes (3 homozygous) at a frequency of 0.002126 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 101 of 10314 chromosomes (freq: 0.009793), Latino in 103 of 35214 chromosomes (freq: 0.002925), European (non-Finnish) in 354 of 128070 chromosomes (freq: 0.002764), Other in 18 of 7128 chromosomes (freq: 0.002525), African in 13 of 24308 chromosomes (freq: 0.000535), South Asian in 6 of 30404 chromosomes (freq: 0.000197) and European (Finnish) in 1 of 25054 chromosomes (freq: 0.00004); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu361 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
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not specified Benign:1Other:1
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at