Submissions for variant NM_024675.4(PALB2):c.833_834delinsAT (p.Leu278His)

dbSNP: rs587778582

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131311	SCV000186284	likely benign	Hereditary cancer-predisposing syndrome	2021-07-15	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.
GeneDx	RCV000160815	SCV000211488	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter protein structure/function; Identified in individuals with breast or gastric cancer, but also in unaffected controls (Carreo et al., 2020; Dorling et al., 2021; Moradian et al., 2021; Muhammad et al., 2022; Subaolu et al., 2023); This variant is associated with the following publications: (PMID: 31159747, 33512806, 24728327, 33558524, 19369211, 33471991, 36605468, 36175305)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204991	SCV000260505	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 278 of the PALB2 protein (p.Leu278His). This variant is present in population databases (rs587778582, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 31159747, 33558524, 36175305). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in PALB2 in an individual who was not affected with recessive PALB2-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 134992). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Counsyl	RCV000204991	SCV000488371	uncertain significance	Familial cancer of breast	2016-03-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131311	SCV000686078	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This variant causes a 2-basepair substitution that results in a single amino acid change, replacing leucine with histidine at codon 278 of the PALB2 protein. This variant can also be described as c.833_834inv and chr16.GRCh37:g.23647033_23647034inv. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 33558524; doi.org/10.7197/cmj.vi.623656), an individual affected with diffuse gastric cancer (PMID: 33512806) and an individual unaffected with cancer (PMID: 31422574). This variant also has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011118). This variant has been identified in 14/251426 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.
GeneKor MSA	RCV000131311	SCV000822120	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477318	SCV002780569	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121746	SCV003928584	uncertain significance	not specified	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.833_834delinsAT (p.Leu278His) is a multinucleotide variant combination of 16-23647033-T-A (synonymous variant, NM_024675.4(PALB2):c.834A>T, p.Leu278=) in phase with 16-23647034-A-T (missense variant, NM_024675.4(PALB2):c.833T>A, p.Leu278Gln) that when combined results in this non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele is estimated at a frequency of 5.6e-05 in 251426 control chromosomes based on an identical allele frequency of each individual component in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.6e-05 vs 0.00016), allowing no conclusion about variant significance. c.833_834delinsAT has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Breast and/or Ovarian Cancer (example, Tsaousis_2019, Moradian_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315409	SCV004015182	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing	The PALB2 gene sequence change deletes 2 nucleotides and inserts 2 nucleotides in exon 4 of the PALB2 mRNA (c.833_834delTAinsAT), replacing leucine with histidine at codon 278 of the PALB2 protein (p.Leu278His). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is reported as two separate single-nucleotide changes in population databases (c.833T>A, ExAC 0.04% and c.833A>T, ExAC 0.04%). This variant has not been reported in the literature in individuals with PALB2-related disease. ClinVar contains an entry for this variant (Variation ID: 134992). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly damaging"; Align-GVGD: "Class C0"). Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000204991	SCV004019669	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
PreventionGenetics, part of Exact Sciences	RCV004528835	SCV004103913	uncertain significance	PALB2-related disorder	2023-10-05	criteria provided, single submitter	clinical testing	The PALB2 c.833_834delinsAT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in an individual undergoing hereditary cancer panel testing, an individual with breast cancer, and an individual with diffuse gastric cancer (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747; Table 2, Moradian et al. 2021. PubMed ID: 33558524; Table 1, Carreño et al. 2020. PubMed ID: 33512806). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of uncertain significance and likely benign in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/134992/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000160815	SCV005331126	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing
ITMI	RCV000121746	SCV000085944	not provided	not specified	2013-09-19	no assertion provided	reference population
Center of Medical Genetics and Primary Health Care	RCV001005025	SCV000987281	uncertain significance	Malignant tumor of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A non-functional domain (200- 394 aa) between DNA binding and CHAM functional domains. Hot-spot has 21 non-VUS coding variants (12 pathogenic and 9 benign), pathogenicity = 57.1%, proximity score 6.742 > threshold 2.472. PM2 Pathogenic Moderate: Variant not found in GnomAD exomes. Variant not found in GnomAD genomes. PP4 Pathogenic Supporting: Female patient was diagnoed with breast cancer at the age of 41 y.o. with strong family history of breast cancer BP4 Benign Supporting: 1 benign prediction from GERP vs no pathogenic predictions." 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.