rs370422990

chr16-23630455-G-Achr16-23630455-G-Cchr16-23630455-G-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.1699C>T(p.His567Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,612,190 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H567N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:6
• Conservation: PhyloP100: -1.03

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=0.028555512).
• BP6: Variant 16-23630455-G-A is Benign according to our data. Variant chr16-23630455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126622.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8, Benign=1}. Variant chr16-23630455-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.1699C>T	p.His567Tyr	missense_variant	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.1699C>T	p.His567Tyr	missense_variant	5/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

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: 0.00

GnomAD3 exomes AF: 0.0000689 AC: 17 AN: 246902 Hom.: 0 AF XY: 0.0000672 AC XY: 9 AN XY: 133978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000994

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1460028 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 726334

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 03, 2022	The p.H567Y variant (also known as c.1699C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 1699. The histidine at codon 567 is replaced by tyrosine, an amino acid with similar properties. This alteration was detected in 1/565 unilateral breast cancer patients, but not in 559 bilateral breast cancer patients (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). In another study, this variant was not detected in a total of 1995 breast cancer cases, but was detected in 1/1998 healthy controls (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). In another study, this alteration was observed in 0/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 04, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, as well as unaffected controls (Tischkowitz et al., 2012; Tung et al., 2015; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25186627, 22241545, 26283626, 26315354, 31843900, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 14, 2023	In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 22241545 (2012), 25186627 (2015), 33471991 (2021) see also LOVD (http://databases.lovd.nl/PALB2), 35263119 (2022)) and in healthy individuals (PMIDs: 26283626 (2015), 26315354 (2015), 33471991 (2021) see also LOVD (http://databases.lovd.nl/PALB2)). The frequency of this variant in the general population, 0.001 (10/9914 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2022	Variant summary: PALB2 c.1699C>T (p.His567Tyr) 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 7.5e-05 in 254898 control chromosomes, predominantly at a frequency of 0.001 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 6 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 Ashkenazi Jewish origin. c.1699C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as in controls (Tischkowitz_2012, Thompson_2015, Ramus_2015, Tung_2015, Dorling_2021, Delahunty_2022). These reports 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. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -

PALB2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

The PALB2 c.1699C>T variant is predicted to result in the amino acid substitution p.His567Tyr. This variant has been reported in several individuals with breast cancer (Tischkowitz et al. 2012. PubMed ID: 22241545; Tung et al. 2015. PubMed ID: 25186627; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991), but it has also been documented in multiple unaffected individuals in several large breast/ovarian cancer case-control studies (Thompson et al. 2015. PubMed ID: 26283626; Ramus et al. 2015. PubMed ID: 26315354; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.10% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126622). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group N Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 20, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.046
Dann	Benign	0.21
DEOGEN2	Benign	0.0075	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.020	N;N
Sift	Benign	0.23	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.059	.;B
Vest4		0.20
MVP		0.19
MPC		0.13
ClinPred		0.030	T
GERP RS		-8.3
Varity_R		0.030
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370422990; hg19: chr16-23641776;