Variant rs45543843 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 16-23629954-T-A is Benign according to our data. Variant chr16-23629954-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126640.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}. Variant chr16-23629954-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2200A>T	p.Thr734Ser	missense_variant	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2200A>T	p.Thr734Ser	missense_variant	5/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

10

AN:

152064

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

13

AN:

251490

Hom.:

0

AF XY:

0.0000662

AC XY:

9

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461894

Hom.:

0

Cov.:

32

AF XY:

0.000180

AC XY:

131

AN XY:

727248

show subpopulations

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:

0.000248

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000658

AC:

10

AN:

152064

Hom.:

0

Cov.:

32

AF XY:

0.0000539

AC XY:

4

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000602

Hom.:

0

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4Benign:2

Uncertain significance, 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered likely 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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 16, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This missense variant replaces threonine with serine at codon 734 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). A functional study has reported that this variant does not impact PALB2 function in a homology-directed repair assay (PMID: 31636395). This variant has been reported in at least 8 individuals affected with breast cancer, 1 individual affected with ovarian cancer and at least 7 individuals unaffected with breast or ovarian cancer (PMID: 17200668, 20091115, 22241545, 25186627, 26283626, 26315354, 26898890, 33471991) including two individuals age 70 years or older without cancer in the FLOSSIES database. This variant also has been reported in individuals affected with pancreatic cancer (PMID: 28767289, 32659497). This variant has been identified in 16/282876 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 05, 2023	The p.T734S variant (also known as c.2200A>T), located in coding exon 5 of the PALB2 gene, results from an A to T substitution at nucleotide position 2200. The threonine at codon 734 is replaced by serine, an amino acid with similar properties. This variant has been identified in numerous disease cohorts as well and unaffected control groups across studies (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Sauty de Chalon A et al. Breast Cancer Res. Treat. 2010 May;121:253-5; Thompson ER et al. Breast Cancer Res, 2015 Aug;17:111; Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Caminsky NG et al. Hum Mutat, 2016 07;37:640-52; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Wiltshire T et al. Genet. Med., 2019 Oct). This amino acid position is highly 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2023	Observed in multiple individuals with breast or pancreatic cancer (Sauty de Chalon et al., 2010; Tischkowitz et al., 2012; Tung et al., 2015; Caminsky et al., 2016; Shindo et al., 2017; Bhai et al., 2021); Observed at comparable frequencies in control populations and in individuals with breast, ovarian, or other cancers (Rahman et al., 2007; Ramus et al., 2015; Thompson et al., 2015; Decker et al., 2017; Pritchard et al., 2018; Song et al., 2020); Published functional studies suggest no damaging effect: HDR activity comparable to wild type (Wiltshire et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 17200668, 20091115, 26283626, 25186627, 22241545, 26315354, 28779002, 28767289, 28440294, 28873162, 29641532, 32659497, 32546565, 22941656, 31636395, 34326862) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 28, 2021

Variant summary: PALB2 c.2200A>T (p.Thr734Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 264516 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.8e-05 vs 0.00016), allowing no conclusion about variant significance. c.2200A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rahman_2007, Sauty de Chalon_2010, , Tischkowitz_2012,Tung_2014, Thompson_2015, Ramus_2015, Caminsky_2016, Shindo_2017, and Lattimore_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported [CHEK2 c.1100delC, p.T367fs*15 (internal testing); BRCA2 c.1929delG, p.Arg645fsX15 (Tung_2014)], providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function which showed the variant to have proficient HDR activity, providing supporting evidence for a benign role (Wiltshire_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Endometrial carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.22

T

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;D

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.032

D

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.66

T

MutationTaster

Benign

0.87

D

PrimateAI

Benign

0.39

T

PROVEAN

Uncertain

-2.4

N;D

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.22

T;D

Polyphen

1.0

.;D

Vest4

0.58

MutPred

0.28

.;Gain of disorder (P = 0.072);

MVP

0.74

MPC

0.33

ClinPred

0.48

T

GERP RS

6.0

Varity_R

0.47

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

rs45543843

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over