Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Lee, Ning-Yuan; Hum, Melissa; Zihara, Sabna; Wang, Lanying; Myint, Matthew K.; Lim, Darren Wan-Teck; Toh, Chee-Keong; Skanderup, Anders; Samol, Jens; Tan, Min-Han; Ang, Peter; Lee, Soo-Chin; Tan, Eng-Huat; Lai, Gillianne G. Y.; Tan, Daniel S. W.; Yap, Yoon-Sim; Lee, Ann S. G.

doi:10.1186/s40246-023-00510-7

Human Genomics

Table 2 List of newly classified pathogenic or likely pathogenic variants and their corresponding ACMG-AMP criteria

From: Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Gene	Variant	Classification	Consequence		Computational and Predictive Data								Population data
				PVS1^a	PS1^a	PM5^a	PM4^a	PP3^a (predictions)					PM2	PS4^a (enriched in cases)
								REVEL^b	CADD^b	SIFT^b	MUTA^b	PLPH^b		B&L^c		BR^d		LU^e
								REVEL^b	CADD^b	SIFT^b	MUTA^b	PLPH^b		vs GN^f	vs SG^g	vs GN^f	vs SG^g	vs GN^f	vs SG^g
EXT2	chr11:g.44109284G > C	Pathogenic	Splice site	✓					✓		✓		✓	**	**
BRIP1	rs1426528935 (T)	Pathogenic	Fr. del	✓					✓		✓			**	**			*	*
FANCA	rs755104393 (G)	Pathogenic	Splice site	✓					✓		✓			*	*
WWOX	rs758588684 (C)	Pathogenic	Startloss	✓					✓	✓	✓	✓		*
GATA2	rs1166272013 (G)	Pathogenic	Splice site	✓									✓	**	**
ERCC6/PGBD3	rs181055741 (A)	Pathogenic	Stopgain	✓											*
TP53	rs1019340046 (G)	Pathogenic	Nonsyn. SNV		✓	✓		✓					✓	**	**
GPC3	rs1158430569 (T)	Likely pathogenic	Nonsyn. SNV			✓								*	**				*
MSH2	rs768572053 (G)	Likely pathogenic	Nonsyn. SNV			✓								*	*
WRN	rs569405870 (A)	Likely pathogenic	Nonsyn. SNV			✓								*	*
PTEN	chr10:g.87864072TCTA > T	Likely pathogenic	Non-fr. del				✓						✓		*
FANCI	rs747603151 (T)	Likely pathogenic	Non-fr. del				✓							*	*			*
KMT2A	chr11:g.118436698C > CGCG	Likely pathogenic	Non-fr. ins				✓							*	*

Fr., frameshift; del., deletion; ins., insertion; ✓, the variant of this row satisfies the criteria of this column; *, the variant of this row is enriched in cases over controls at p < 0.05; **, the variant of this row is enriched in cases over controls at p < 0.01
^aPVS1, predicted null variant in a gene where loss of function is a known mechanism of disease; PS1, same amino acid change as an established pathogenic variant; PM5, novel missense change at an amino acid residue where a different pathogenic missense change has been seen before; PM4, protein length changing variant; PP3, multiple lines of computational evidence support a deleterious effect on the gene/gene product; PM2, absent in population databases gnomAD v2.1.1 non-cancer East Asians (EAS) and SG10K_Health; PS4, prevalence in affected statistically increased over controls
^bREVEL, if all protein changes have REVEL score greater than 0.68; CADD, if the scaled CADD score is greater than 20; SIFT, if SIFT predicts that this variant is pathogenic; MUTA, if MutationTaster predicts that this variant is pathogenic; PLPH, if PolyPhen-2 HDIV or HVAR predicts that this variant is pathogenic
^cB&L, the cohort of 55 patients with dual breast and lung cancer
^dBR, the cohort of 290 early-onset or familial breast cancer patients from Singapore
^eLU, the cohort of 209 lung cancer adenocarcinoma patients from Singapore
^fvs GN, in a Fisher’s Exact Test of allele frequencies against 9,626 non-cancer exomes and whole-genomes of the gnomAD v2.1.1 East Asian (EAS) subpopulation
^gvs SG, in a Fisher’s Exact Test of allele frequencies against 9,770 whole-genomes from healthy Singaporean volunteers from SG10K_Health

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