Submissions for variant NM_000057.4(BLM):c.968A>G (p.Lys323Arg)

gnomAD frequency: 0.00056  dbSNP: rs146504061

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656781	SCV000149235	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226028	SCV000283158	uncertain significance	Bloom syndrome	2025-02-03	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000575545	SCV000672880	likely benign	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV003492470	SCV000838954	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000226028	SCV000896480	uncertain significance	Bloom syndrome	2022-04-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000226028	SCV001275083	uncertain significance	Bloom syndrome	2017-04-28	criteria provided, single submitter	clinical testing	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656781	SCV002010746	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120244	SCV002068155	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000575545	SCV002533179	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656781	SCV002774442	uncertain significance	not provided	2024-04-23	criteria provided, single submitter	clinical testing	The BLM c.968A>G (p.Lys323Arg) variant has been reported in the published literature in individuals affected with prostate cancer (PMID: 35892882 (2022)), breast cancer (PMID: 35264596 (2022), 23028338 (2012)), colon polyps (PMID: 33436027 (2021)), mesothelioma and/or melanoma (PMID: 33318203 (2020)), neuroblastoma (PMID: 26580448 (2015)), and Li-Fraumeni syndrome (PMID: 22829774 (2012)). This variant was also identified in an individual with high-grade serous ovarian cancer (HGSC) that carried two other pathogenic variants in the BRCA1 and RAD51C genes (PMID: 36232793 (2022)). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120244	SCV004020856	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000226028	SCV004031227	uncertain significance	Bloom syndrome	2024-09-06	criteria provided, single submitter	clinical testing	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.
ITMI	RCV000120244	SCV000084393	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656781	SCV001550753	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Natera, Inc.	RCV000226028	SCV002089995	uncertain significance	Bloom syndrome	2017-10-17	no assertion criteria provided	clinical testing