16-23629645-C-T

Variant names:

• chr16-23629645-C-T
• rs587778587
• NM_024675.4:c.2509G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024675.4(PALB2):​c.2509G>A​(p.Glu837Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:12 O:1
• Conservation: PhyloP100: 0.360

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028042644).
• BP6: Variant 16-23629645-C-T is Benign according to our data. Variant chr16-23629645-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128133.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=4, not_provided=1}. Variant chr16-23629645-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000127 (185/1461536) while in subpopulation EAS AF= 0.00433 (172/39698). AF 95% confidence interval is 0.0038. There are 0 homozygotes in gnomad4_exome. There are 89 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2509G>A	p.Glu837Lys	missense_variant	Exon 5 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2509G>A	p.Glu837Lys	missense_variant	Exon 5 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250516 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135656

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

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: 0.000127 AC: 185 AN: 1461536 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89 AN XY: 727100

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74328

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:4

Jun 15, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 15, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2018

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:3 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Sep 04, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.2509G>A (p.Glu837Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250516 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. Specifically, the variant allele was detected at a frequency of 0.0042 within Korean controls (gnomAD) and at a frequency range of 0.0058-0.0069 within Japanese controls (Momozawa_2018 and HGVD and jMorp databases). Therefore, the observed variant frequency within East Asian control individuals is at least 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though c.2509G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Nakagomi 2016, Kim 2017, Sato 2017, Shin_2020) and in a patient with Beckwith-Wiedemann syndrome and hepatoblastoma (Kim 2017), these patients were all of East Asian origin. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA1 c.188T>A, p.L63X; PTEN c.697C>T, p.Arg233X; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2018

Leiden Open Variation Database

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Familial cancer of breast Benign:2

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Breast and/or ovarian cancer Uncertain:1

May 21, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

PALB2-related disorder Benign:1

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Feb 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26411315, 29190888, 24728327, 24755471, 27783279, 24163242, 28796317, 29338689) -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Glu837Lys variant was identified in 5 of 780 proband chromosomes (frequency: 0.0064) from individuals or families with breast cancer and was present in 1 of 124 control chromosomes (frequency: 0.008) from healthy individuals (Kim 2017, Nakagomi 2016). The variant was also identified in dbSNP (ID: rs587778587) as “With Pathogenic, other allele”, ClinVar (6x, as likely benign by Invitae, Ilummina, uncertain significance by Ambry Genetics, GeneDx, and ITMI), Clinvitae (4x), Cosmic (1x, large intestine, prostate, carcinoma), databases. The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 30 of 276582 chromosomes at a frequency of 0.000108 in the following populations: African in 6 of 25030 chromosomes (freq. 0.00024), East Asian in 24 of 18870 chromosomes (freq. 0.0013), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic BRCA2 variant (c.4042delT, p.Cys1348ValfsX26) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.Glu837Lys variant does not have clinical significance The p.Glu837Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.044
Sift	Benign	0.14	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.92	.;P
Vest4		0.29
MutPred		0.14		.;Gain of ubiquitination at E837 (P = 0.0037);
MVP		0.49
MPC		0.083
ClinPred		0.045	T
GERP RS		2.4
Varity_R		0.032
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs587778587; hg19: chr16-23640966; COSMIC: COSV55163483;