rs200048921

Positions:

• chr16-23637952-G-A
• chr16-23637952-G-C
• chr16-23637952-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_024675.4(PALB2):​c.109C>T​(p.Arg37Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000548 in 1,460,624 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 0.9863
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 5.53

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]

PALB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.109C>T	p.Arg37Cys	missense_variant, splice_region_variant	3/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.109C>T	p.Arg37Cys	missense_variant, splice_region_variant	3/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460624 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 05, 2019	The PALB2 c.109C>T; p.Arg37Cys variant (rs200048921) is reported in the literature in at least one individual with breast cancer (Tung 2016), but is also reported in healthy controls (Momozawa 2018). This variant is reported in ClinVar (Variation ID: 220218). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 37 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two different variants at this codon (Arg37His, Arg37Ser) are reported in individuals with breast cancer (Foo 2017, Lerner-Ellis 2017), and the Arg37His variant protein was shown to have impaired homologous recombination-mediated DNA repair activity but unaffected PALB2-BRCA1 interaction (Lerner-Ellis 2017). Given the limited information regarding p.Arg37Cys, its clinical significance is uncertain at this time. REFERENCES Foo TK et al. Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. Oncogene. 2017 Jul 20;36(29):4161-4170. Lerner-Ellis J et al. A high frequency of PALB2 mutations in Jamaican patients with breast cancer. Breast Cancer Res Treat. 2017 Apr;162(3):591-596. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2017	This variant is denoted PALB2 c.109C>T at the cDNA level, p.Arg37Cys (R37C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in at least one individual with breast cancer (Tung 2016). PALB2 Arg37Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Arg37Cys is located in regions of interaction with RAD51 and BRCA1 (Sy 2009, Buisson 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Arg37Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Oct 10, 2018	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 37 of the PALB2 protein (p.Arg37Cys). This variant is present in population databases (rs200048921, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 33811135). ClinVar contains an entry for this variant (Variation ID: 220218). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31636395, 33811135). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2022	This missense variant replaces arginine with cysteine at codon 37 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 an individual affected with breast cancer (PMID: 26976419) and also in two breast cancer case-control studies in which this variant was detected in 1/11241 unaffected individuals and absent in 7051 female breast cancer cases (PMID: 30287823) and in 3/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010550). This variant also has been reported in a pancreatic cancer case-control study in 1/23705 unaffected individuals and absent in 1005 cases (PMID: 32980694). This variant has been identified in 1/251456 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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2024	This alteration is classified as 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

PALB2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The PALB2 c.109C>T variant is predicted to result in the amino acid substitution p.Arg37Cys. This variant was reported as a variant of uncertain significance in patients with breast cancer (Wiltshire et al. 2019. PubMed ID: 31636395; Table A2, Tung et al. 2016. PubMed ID: 26976419; Ng et al. 2021. PubMed ID: 33811135) but has also been described in apparently healthy controls (Supplementary Data 1, Momozawa et al. 2018. PubMed ID: 30287823; Ng et al. 2021. PubMed ID: 33811135; Okawa et al. 2023. PubMed ID: 36243179, supplementary data). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220218/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.34		Loss of catalytic residue at R37 (P = 0.1727);.;
MVP		0.88
MPC		0.39
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.49
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs200048921; hg19: chr16-23649273; COSMIC: COSV99849123; COSMIC: COSV99849123;