16-23607864-C-T

Variant names:

• chr16-23607864-C-T
• rs876659859
• NM_024675.4:c.3350G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5_Supporting PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3350G>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1117 (p.Arg1117Lys); however, RNA analysis demonstrated that the variant impacts splicing, leading to exon 12 skipping (r.3202_3350del149, p.Gly1068ValfsTer5) and a translational frameshift with 100% allele bias and no wild-type splice events harboring the variant (Ambry Genetics). The resulting mRNA is not predicted to undergo nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been observed in combination with a PALB2 exon 11 duplication, which is classified as pathogenic, in at least four adult individuals without Fanconi Anemia (Ambry Genetics and Invitae). Although the phase of the variants was not confirmed, evidence from these individuals was not used to apply BS2 on the basis that multiple co-occurrences of this variant with the exon 11 duplication in unrelated individuals suggests these variants are more likely to be in cis. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM2_Supporting, PM5_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10579920/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:4
• Conservation: PhyloP100: 5.18

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3350G>A	p.Arg1117Lys	missense_variant, splice_region_variant	Exon 12 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3350G>A	p.Arg1117Lys	missense_variant, splice_region_variant	Exon 12 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:2 Uncertain:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2023

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3350G>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1117 (p.Arg1117Lys); however, RNA analysis demonstrated that the variant impacts splicing, leading to exon 12 skipping (r.3202_3350del149, p.Gly1068ValfsTer5) and a translational frameshift with 100% allele bias and no wild-type splice events harboring the variant (Ambry Genetics). The resulting mRNA is not predicted to undergo nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been observed in combination with a PALB2 exon 11 duplication, which is classified as pathogenic, in at least four adult individuals without Fanconi Anemia (Ambry Genetics and Invitae). Although the phase of the variants was not confirmed, evidence from these individuals was not used to apply BS2 on the basis that multiple co-occurrences of this variant with the exon 11 duplication in unrelated individuals suggests these variants are more likely to be in cis. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM2_Supporting, PM5_Supporting) -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1117 of the PALB2 protein (p.Arg1117Lys). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26564480, 30303537). ClinVar contains an entry for this variant (Variation ID: 232594). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 12 and introduces a new termination codon (internal data). However the mRNA is not expected to undergo nonsense-mediated decay. 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 Pathogenic:1 Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3350G>A variant (also known as p.R1117K), located in coding exon 12 of the PALB2 gene, results from a G to A substitution at nucleotide position 3350. The arginine at codon 1117 is replaced by lysine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12 and may have some effect on normal mRNA splicing. This alteration was identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration at this donor site, c.3350+5G>A, has been identified in the homozygous state in an individual with Fanconi Anemia features (Mori M et al. Haematologica, 2019 Oct;104:1962-1973). RNA studies of the c.3350+5G>A variant showed expression of the same abnormal transcript in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Nov 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A likely pathogenic mutation was detected in the PALB2 gene. The c.3350G>A variant (also known as p.R1117K), located in coding exon 12 of the PALB2 gene, results from a G to A substitution at nucleotide position 3350. This change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. Using the ESE and Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to weaken the native splice donor site (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration at this donor site, c.3350+5G>A has been identified in the homozygous state in an individual with Fanconi Anemia features (Mori M et al. Haematologica, 2019 Oct;104:1962-1973). This variant has been observed in individual(s) with breast cancer (PMID: 26564480, 30303537). ClinVar contains an entry for this variant (Variation ID: 232594). Therefore, this variant has been classified as likely pathogenic. -

not provided Pathogenic:1

Aug 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.3350G>A (p.Arg1117Lys) variant alters the last nucleotide of exon 12 in PALB2, and has been described to be pathogenic and causing aberrant splicing/translational frameshift of the transcript (ClinGen Variant Curation Expert Panel, https://erepo.clinicalgenome.org/evrepo/). In the published literature, this variant has been reported in numerous individuals with breast cancer (PMIDs: 37686625 (2023), 35264596 (2022), 30303537 (2019), 26564480 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as likely pathogenic. -

not specified Uncertain:1

Jun 09, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.3350G>A (p.Arg1117Lys) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Three computational tools predict no significant impact on splicing and one predicts the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251412 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3350G>A has been reported in the literature in individuals affected with breast cancer (example Damiola_2015, Girard_2019, Guindalini_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical-significance assessments for this variant have been submitted to ClinVar after 2014 . Three laboratories classified the variant as likely pathogenic, and two classified it as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Aug 10, 2022

Oncological Genetic Counseling Clinic, "Carlo Poma" Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: in vivo

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.061	T;T
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.45		.;Gain of methylation at R1117 (P = 0.0114);
MVP		0.76
MPC		0.16
ClinPred		0.86	D
GERP RS		6.1
Varity_R		0.41
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs876659859; hg19: chr16-23619185;