rs587778582

chr16-23635712-TA-AT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_024675.4(PALB2):c.833_834delinsAT(p.Leu278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L278Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2 O:1
• Conservation: PhyloP100: 0.421

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-23635712-TA-AT is Benign according to our data. Variant chr16-23635712-TA-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134992.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.833_834delinsAT	p.Leu278His	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.833_834delinsAT	p.Leu278His	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2021	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	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2023	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. -

Familial cancer of breast Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	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]. -

not specified Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2023	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 22, 2022

- -

PALB2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2023

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. -

Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2023

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) -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778582; hg19: chr16-23647033;