chr15-90760688-A-G
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000057.4(BLM):c.1315A>G(p.Met439Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M439I) has been classified as Likely benign.
Frequency
Consequence
NM_000057.4 missense
Scores
Clinical Significance
Conservation
Publications
- Bloom syndromeInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
- osteosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary nonpolyposis colon cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152212Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000251 AC: 63AN: 251248 AF XY: 0.000228 show subpopulations
GnomAD4 exome AF: 0.000126 AC: 184AN: 1461758Hom.: 1 Cov.: 31 AF XY: 0.000132 AC XY: 96AN XY: 727196 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000105 AC: 16AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74364 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:2Benign:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -
not provided Uncertain:1Benign:2
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In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in patients referred for hereditary cancer genetic testing (PMID: 31159747); This variant is associated with the following publications: (PMID: 31159747) -
BLM: BP4 -
Hereditary cancer-predisposing syndrome Benign:3
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Benign:2
Variant summary: BLM c.1315A>G (p.Met439Val) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00012 in 1613970 control chromosomes, predominantly at a frequency of 0.0044 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035). c.1315A>G has been reported as a VUS in at least one individual undergoing multigene panel testing for a suspected hereditary cancer predisposition syndrome (Tsaousis_2019), but to our knowledge has not been observed in individual(s) affected with Bloom Syndrome. This report does not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 127475). Based on the evidence outlined above, the variant was classified as likely benign. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at