Submissions for variant NM_024675.4(PALB2):c.1881G>T (p.Val627=)

dbSNP: rs139362268

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212802	SCV000170852	benign	not specified	2013-12-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000127291	SCV000213030	likely benign	Hereditary cancer-predisposing syndrome	2014-09-05	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030265	SCV000253587	benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127291	SCV000537438	likely benign	Hereditary cancer-predisposing syndrome	2015-06-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590744	SCV000601745	benign	not provided	2022-12-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212802	SCV000699547	benign	not specified	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1881G>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 246196 control chromosomes, predominantly at a frequency of 0.0028 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 18-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1881G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Catucci_2012, Hofstatter_2011) with limited information (ie, lack of co-occurrence and cosegregation data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000127291	SCV002530655	likely benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590744	SCV002545767	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Fulgent Genetics, Fulgent Genetics	RCV002483179	SCV002804314	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-07-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000127291	SCV002819246	likely benign	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149778	SCV003838088	likely benign	Breast and/or ovarian cancer	2021-12-07	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030265	SCV001193163	likely benign	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356841	SCV001552112	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PALB2 p.Val627Val variant was identified in 2 of 378 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Hofstatter_2011_21365267, Catucci_2012_22692731). The variant was also identified in the following databases: dbSNP (ID: rs139362268) as “With Likely benign allele” ,ClinVar (2x as benign by GeneDx, Invitae, 4x as likely benign by Ambry Genetics, Color Genomics, Quest Diagnostics, Palb2 database), Clinvitae (3x as benign and likely benign by ClinVar), LOVD 3.0 (3x "probably does not affect function"). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 32 of 246196 chromosomes at a frequency of 0.00013 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5482 chromosomes (freq: 0.00018), European Non-Finnish in 3 of 111674 chromosomes (freq: 0.00003), Ashkenazi Jewish in 28 of 9848 chromosomes (freq: 0.003), while the variant was not observed in the African, Latino, East Asian, European Finnish, and South Asian populations. The p.Val627Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358083	SCV001553732	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PALB2 p.Val627Val variant was identified in 2 of 378 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Hofstatter_2011_21365267, Catucci_2012_22692731). The variant was also identified in the following databases: dbSNP (ID: rs139362268) as “With Likely benign allele” ,ClinVar (2x as benign by GeneDx, Invitae, 4x as likely benign by Ambry Genetics, Color Genomics, Quest Diagnostics, Palb2 database), Clinvitae (3x as benign and likely benign by ClinVar), LOVD 3.0 (3x "probably does not affect function"). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 32 of 246196 chromosomes at a frequency of 0.00013 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5482 chromosomes (freq: 0.00018), European Non-Finnish in 3 of 111674 chromosomes (freq: 0.00003), Ashkenazi Jewish in 28 of 9848 chromosomes (freq: 0.003), while the variant was not observed in the African, Latino, East Asian, European Finnish, and South Asian populations. The p.Val627Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.