16-23636146-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_024675.4(PALB2):c.400G>A(p.Asp134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. D134E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 0.0800

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004504204).
• BP6: Variant 16-23636146-C-T is Benign according to our data. Variant chr16-23636146-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126749.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=5}. Variant chr16-23636146-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.400G>A	p.Asp134Asn	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.400G>A	p.Asp134Asn	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 151876 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 250744 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135498

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1460730 Hom.: 1 Cov.: 32 AF XY: 0.0000936 AC XY: 68 AN XY: 726560

Gnomad4 AFR exome AF: 0.00402

Gnomad4 AMR exome AF: 0.000225

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: 0.00000180

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00149 AC: 227 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74296

Gnomad4 AFR AF: 0.00530

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000240 Hom.: 1

Bravo AF: 0.00153

ESP6500AA AF: 0.00546 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2016	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Asp134Asn variant was identified in 5 of 8290 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer or Lynch syndrome and was present in 1 of 4520 control chromosomes (frequency: 0.0003) from healthy individuals (Thompson 2015, Tung 2016, Yadav 2017, Yurgelun 2015, Zheng 2012). The variant was identified in dbSNP (ID: rs139555085) as “With other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano and Color; as uncertain significance by Cancer Genetics Laboratory/Peter MacCallum Cancer Centre; and as likely pathogenic by PALB2 database) and LOVD 3.0. The variant was also identified in control databases in 116 of 276502 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 110 of 24004 chromosomes (freq: 0.005, increasing the likelihood this could be a low frequency benign variant), Latino in 5 of 34282 chromosomes (freq: 0.0001) and European in 1 of 126534 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp134 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Asn variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The PALB2 c.400G>A (p.Asp134Asn) variant involves the alteration of a non-conserved nucleotide and 5/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 54/125366 control chromosomes, predominantly observed in the African cohort at a frequency of 0.004997 (52/10406). This frequency is about 32 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of co-occurrence and/or cosegregation data). An internal LCA sample reports the variant to co-occur with a pathogenic PMS2 variant, c.2186_2187delTC (p.Leu729fs - classified as pathogenic by LCA). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	This variant is associated with the following publications: (PMID: 31757951, 23555315, 28767289, 27878467, 25186627, 25980754, 26283626, 26979391, 21932393, 32659497) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2022	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 05, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 23, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 04, 2022

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 26, 2021

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	11
Dann	Benign	0.88
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.041
Sift	Benign	0.38	T
Sift4G	Benign	0.49	T
Polyphen		0.019	B
Vest4		0.12
MVP		0.24
MPC		0.089
ClinPred		0.00066	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139555085; hg19: chr16-23647467; COSMIC: COSV55162498; COSMIC: COSV55162498;