Submissions for variant NM_024675.4(PALB2):c.2674G>A (p.Glu892Lys)

gnomAD frequency: 0.00004  dbSNP: rs45476495

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131257	SCV000186221	likely benign	Hereditary cancer-predisposing syndrome	2020-11-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114549	SCV000260420	likely benign	Familial cancer of breast	2025-01-29	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114549	SCV000268016	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000587708	SCV000566596	uncertain significance	not provided	2024-03-03	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, pancreatic, or other cancers (PMID: 17200668, 22241545, 26689913, 25575445, 26315354, 26283626, 25186627, 25980754, 25356972, 26534844, 28779002, 28503720, 29368341, 31742824, 32853339); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 28503720, 25575445, 25356972, 17200668, 26283626, 25980754, 22241545, 25186627, 26534844, 28779002, 29368341, 26689913, 30287823, 32853339, 33471991, 32830346, 31742824, 30982232, 30113427, 24485656, 19609323, 20871615, 36243179)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587708	SCV000601768	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00015 (19/129192 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMID: 30982232 (2019), 28779002 (2017), 28503720 (2017), 26534844 (2016), 26283626 (2015), 25186627 (2015), 22241545 (2012), and 17200668 (2007)), prostate cancer (PMID: 32853339 (2021) and 29368341 (2018)), and renal cell carcinoma (PMID: 32830346 (2021)). This variant has also been reported in unaffected individuals (PMID: 30287823 (2018) and 28779002 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000131257	SCV000685968	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 892 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17200668, 22241545, 25186627, 26283626, 28503720, 28779002, 33471991, 30982232), pancreatic cancer (PMID: 25356972), Lynch syndrome-associated cancer and colorectal polyps (PMID: 25980754), lung, stomach and prostate cancer (PMID: 26689913, 29368341, 32853339), and also detected in individuals unaffected with cancer (PMID: 28779002, 30287823, 32980694, 31214711, 33471991). In a breast cancer case-control meta-analysis, this variant was reported in 11/60455 cases and 9/53452 unaffected individuals with OR=1.081 (95%CI 0.448 to 2.608) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010215). This variant has been identified in 20/282898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483553	SCV000699574	uncertain significance	not specified	2022-09-08	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2674G>A (p.Glu892Lys) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 278636 control chromosomes (gnomAD, Rahman_2007, Momozawa_2018). This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.5e-05 vs 0.00016), allowing no conclusion about variant significance. c.2674G>A has been reported in the literature in individuals affected with pancreatic cancer, LS-associated cancer and/or colorectal polyps, prostate cancer, inherited renal cell carcinoma and breast cancer and/or ovarian cancer (Rahman_2007, Tischkowitz_2012, Li_2016, Nguyen-Dumont_2015, Thompson_2015, Zhen_2015, Tung_2014, Yurgelun_2015, Rummel_2017, Isaacsson Velho_2018, Wang_2019, Shao_2019, Smith_2020, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was also reported in the FLOSSIES dataset of women over the age of 70 with no history of cancer (carrier frequency=0.0001012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submitters have assessed the variant since 2014: eleven classify the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000114549	SCV000785999	uncertain significance	Familial cancer of breast	2018-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118198	SCV001276464	uncertain significance	Fanconi anemia complementation group N	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000483553	SCV002070218	uncertain significance	not specified	2020-05-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.2674G>A, in exon 7 that results in an amino acid change, p.Glu892Lys. This sequence change has been described in the gnomAD database with a frequency of 0.015% in the European sub-population (dbSNP rs45476495). This sequence change has been reported in individuals with suspected Lynch syndrome, breast, pancreatic, stomach, lung, and prostate cancer (PMIDs: 17200668, 26283626, 22241545, 25356972, 26534844, 28503720, 30287823, 25575445, 26689913, 29368341, 25980754). The p.Glu892Lys change affects a highly conserved amino acid residue located in a domain of the PALB2 protein that is known to be functional. The p.Glu892Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Glu892Lys change remains unknown at this time.
Sema4, Sema4	RCV000131257	SCV002530716	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114549	SCV004019639	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Baylor Genetics	RCV000114549	SCV004202019	uncertain significance	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016385	SCV005646476	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-01-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000483553	SCV005872937	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BS1, BP1
Leiden Open Variation Database	RCV000587708	SCV001193276	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587708	SCV001554246	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Glu892Lys variant was identified in 8 of 9314 proband chromosomes (frequency: 0.0009) from individuals or families with breast and pancreatic cancers and was not identified in 3996 control chromosomes from healthy individuals (Li 2017, Nguyen_Dumont 2015, Thompson 2015, Zhen 2015). The variant was also identified in dbSNP (ID: rs45476495) as with pathogenic, uncertain significance allele; in the ClinVar and Clinvitae databases as with uncertain significance by Ambry Genetics, Invitae, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Study Description, GeneDx, and Quest Diagnostics Nichols Institute San Juan Capistrano. In addition, the variant was identified in the LOVD 3.0 database 4X and in the Zhejiang Colon Cancer database 1X from unknown tissue source. The variant was not identified in the Cosmic and MutDB, databases. The variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles. The variant was identified in control databases in 18 of 277250 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 18 of 126726 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Glu892 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu892Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587708	SCV001741272	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587708	SCV001956569	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483473	SCV004228969	not provided	Familial cancer of breast; Fanconi anemia complementation group N; Familial ovarian cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-30-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004739374	SCV005351222	uncertain significance	PALB2-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The PALB2 c.2674G>A variant is predicted to result in the amino acid substitution p.Glu892Lys. This variant has been reported in individuals with breast cancer and an individual with renal cell carcinoma (Nguyen-Dumont et al. 2015. PubMed ID: 25575445; Table S1, Wang et al. 2019. PubMed ID: 30982232; Table S2, Shao et al. 2020. PubMed ID: 31742824; Supplement, Smith. 2021. PubMed ID: 32830346). It has also been reported in individuals with prostate cancer (Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341; Table S1, Momozawa et al. 2018. PubMed ID: 30287823, Table S1). However, a large cohort study reported this variant displayed no significant association with prostate cancer risk (Table S3, referred to as Chr16:23637631C>T, Darst et al. 2021. PubMed ID: 32853339). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126672/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.