rs146504061

Positions:

chr15-90754819-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000057.4(BLM):c.968A>G(p.Lys323Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2O:1

Conservation

PhyloP100: 3.11

Variant links:

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11627719).

BP6

Variant 15-90754819-A-G is Benign according to our data. Variant chr15-90754819-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.968A>G	p.Lys323Arg	missense_variant	5/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.968A>G	p.Lys323Arg	missense_variant	5/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000371

AC:

AN:

250780

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000732

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000932

AC:

1362

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

671

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000519

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000999

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000859

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 11, 2023	The BLM c.968A>G (p.Lys323Arg) missense change has a maximum subpopulation frequency of 0.07% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BLM protein (p.Lys323Arg). This variant is present in population databases (rs146504061, gnomAD 0.07%). This missense change has been observed in individual(s) with breast cancer (PMID: 23028338). ClinVar contains an entry for this variant (Variation ID: 127518). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 17, 2017	- -

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BLM p.Lys323Arg variant was identified in dbSNP (ID: rs146504061), ClinVar (classified as VUS by Invitae, Ambry Genetics, Mendelics, Fulgent Genetics and GeneDx for Bloom syndrome and Hereditary cancer-predisposing syndrome) and LOVD 3.0 (classified as a VUS) but was not identified in Cosmic. The variant was also found in control databases in 109 of 282184 chromosomes at a frequency of 0.000386 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: European (non-Finnish) in 96 of 128798 chromosomes (freq: 0.000745), Other in 3 of 7198 chromosomes (freq: 0.000417), African in 6 of 24952 chromosomes (freq: 0.000241) and Latino in 4 of 35350 chromosomes (freq: 0.000113), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. This variant was identified in 1/681 healthy individuals in a study assessing variation in cancer genes in a healthy population (Bodian_2014_PMID 24728327). Another study identified the K323R variant in 1/453 cases of breast cancer (Thompson_2012_PMID 23028338). 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.Lys323 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2023	In the published literature, the variant has been reported in individuals with Li-Fraumeni syndrome (PMID: 22829774 (2012)), breast cancer (PMID: 35264596 (2022), 23028338 (2012)), colon polyps (PMID: 33436027 (2021)), mesothelioma and/or melanoma (PMID: 33318203 (2020)), and neuroblastoma (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.0012 (61/50710 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with high grade serous ovarian carcinoma with a family history suggestive of Lynch syndrome, who also harbored pathogenic variants in BRCA1 and RAD51C (Infante et al., 2022); Observed in individuals with personal or family history including breast cancer, renal cell carcinoma, neuroblastoma, mesothelioma, and Lynch syndrome-related cancers (Dalgliesh et al., 2010; Thompson et al., 2012; Zhang et al., 2015; Martin-Morales et al., 2018; Bononi et al., 2020; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24728327, 23028338, 22829774, 28873162, 28944238, 20054297, 30256826, 26580448, 30171174, 33318203, 35264596, 33436027, 36232793, 35892882, 34117267, 33606809) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Uncertain:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2023	Variant summary: BLM c.968A>G (p.Lys323Arg) results in a conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 252142 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.00037 vs 0.0035), allowing no conclusion about variant significance. c.968A>G has been reported in the literature in individuals affected with various cancers without strong evidence of causality, as well as in unaffected controls (e.g. Bodian_2014, Bononi_2020, Guindalini_2022, Infante_2022, Li_2021, Mondschein_82022, Patel_2021, Paulo_2018, Sandoval_2021, Zhang_2015, Martin-Morales_2018). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. Co-occurrence with other pathogenic variants has been reported in an ovarian cancer patient (BRCA1 c.4165_4166del, p.Gln1388_Ser1389insTer; RAD51C c.709C>T, p.Arg237Ter; Infante_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33436027, 36232793, 26580448, 35264596, 24728327, 29659569, 35892882, 34117267, 33318203, 33606809, 30256826). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=10) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2021	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.968A>G, in exon 5 that results in an amino acid change, p.Lys323Arg. This sequence change has been previously described in a family with breast cancer (PMID: 23028338). This sequence change has been described in the gnomAD database with a low population frequency of 0.075% in non-Finnish Europeans (dbSNP rs146504061). The p.Lys323Arg change affects a moderately conserved amino acid residue located in a domain of the BLM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys323Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys323Arg change remains unknown at this time. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2022	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 04, 2022	- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

0.92

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.11

Sift

Benign

0.33

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.99

D;.

Vest4

0.16

MVP

0.86

MPC

0.23

ClinPred

0.13

GERP RS

5.2

Varity_R

0.033

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over